Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (cyano-methyl)-amides inhibitors of cathepsin C

ABSTRACT

This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (cyano-methyl)-amides of formula 1 
                         
and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

FIELD OF INVENTION

This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid(cyano-methyl)-amides of formula 1

and their use as inhibitors of Cathepsin C, pharmaceutical compositionscontaining the same, and methods of using the same as agents fortreatment and/or prevention of diseases connected with dipeptidylpeptidase I activity, e.g. respiratory diseases.

BACKGROUND INFORMATION

-   -   WO2004110988 discloses peptidyl nitrile inhibitors as        dipeptidyl-peptidase I (DPPI) inhibitors for the treatment of a        series of diseases.    -   WO2009074829 and WO2010142985 also disclose peptidyl nitrile        inhibitors as dipeptidyl-peptidase I (DPPI) inhibitors for the        treatment asthma, COPD or allergic rhinitis.

BRIEF SUMMARY OF THE INVENTION

Dipeptidyl-aminopeptidase I (DPPI or Cathepsin C; EC3.4.141), is alysosomal cysteine protease capable of removing dipeptides from theamino terminus of protein substrates. DPPI was first discovered byGutman and Fruton in 1948 (J. Biol. Chem. 174: 851-858, 1948). The cDNAof the human enzyme has been described in 1995 (Paris et al.; FEBS Lett369: 326-330, 1995). The DPPI protein is processed into a matureproteolytically active enzyme consisting of a heavy chain, a lightchain, and a propeptide that remains associated with the active enzyme(Wolters et al.; J. Biol. Chem. 273: 15514-15520, 1998). Whereas theother cysteine Cathepsins (e.g. B, H, K, L and S) are monomers, DPPI isa 200-kD tetramer with 4 identical subunits, each composed of the 3different polypeptide chains. DPPI is constitutively expressed in manytissues with highest levels in lung, kidney, liver and spleen (Kominamiet al.; Biol. Chem. Hoppe Seyler 373: 367-373, 1992). Consistent withits role in the activation of serine proteases from hematopoetic cells,DPPI is also relatively highly expressed in neutrophils, cytotoxiclymphocytes, natural killer cells, alveolar macrophages and mast cells.Recent data from DPPI deficient mice suggest that, besides being animportant enzyme in lysosomal protein degradation, DPPI also functionsas the key enzyme in the activation of granule serine proteases incytotoxic T lymphocytes and natural killer cells (granzymes A and B;Pham et al.; Proc. Nat. Acad. Sci. 96: 8627-8632, 1999), mast cells(chymase and tryptase; Wolter et al.; J. Biol. Chem. 276: 18551-18556,2001), and neutrophils (Cathepsin G, elastase and proteinase 3; Adkisonet al.; J. Clin. Invest. 109: 363.371, 2002). Once activated, theseproteases are capable of degrading various extracellular matrixcomponents, which can lead to tissue damage and chronic inflammation.

Thus, inhibitors of Cathepsin C could potentially be useful therapeuticsfor the treatment of neutrophil-dominated inflammatory diseases such aschronic obstructive pulmonary disease (COPD), pulmonary emphysema,asthma, multiple sclerosis, and cystic fibrosis (Guay et al.; Curr.Topics Med. Chem. 10: 708-716, 2010; Laine and Busch-Petersen; ExpertOpin. Ther. Patents 20: 497-506, 2010). Rheumatoid arthritis is alsoanother chronic inflammatory disease where DPPI appears to play a role.Neutrophils are recruited to the site of joint inflammation and releaseCathepsin G, elastase and proteinase 3, proteases which are believed tobe responsible for cartilage destruction associated with rheumatoidarthritis. Indeed, DPPI deficient mice were protected against acutearthritis induced by passive transfer of monoclonal antibodies againsttype II collagen (Adkison et al.; J. Clin. Invest. 109: 363.371, 2002).

In light of the role DPPI plays in activating certain pro-inflammatoryserine proteases, it seems desirable to prepare compounds that inhibitits activity, which thereby inhibit downstream serine protease activity.It has been surprisingly found that the bicyclic compounds of thepresent invention possess potent Cathepsin C activity, high selectivityagainst other Cathepsins, e.g. Cathepsin K, and in general desirablepharmacokinetic properties.

DETAILED DESCRIPTION OF THE INVENTION

A compound of formula 1

-   wherein-   X is selected from among S and O; preferably S;-   Y is selected from among N or CH, preferably CH;-   R¹ is independently selected from among H, C₁₋₆-alkyl-, halogen,    HO—, C₁₋₆-alkyl-O—, H₂N—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂N— and    C₁₋₆-alkyl-C(O)HN—;-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected from among    -   R^(2.1);    -   aryl-; optionally substituted with one, two or three residues        independently selected from R^(2.1); optionally substituted with        one R^(2.3);    -   C₅₋₁₀-heteroaryl-; containing one, two, three or four        heteroatoms independently selected from among S, S(O), S(O)₂, O        and N, wherein carbon atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.1); wherein nitrogen atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.2); wherein a carbon atom of the ring is optionally        substituted with one R^(2.3); a nitrogen atom of the ring is        optionally substituted with one R^(2.4);    -   C₅₋₁₀-heterocyclyl-; containing one, two, three or four        heteroatoms independently selected from among S, S(O), S(O)₂, O        and N, wherein the ring is fully or partially saturated, wherein        carbon atoms of the ring are optionally and independently from        each other substituted with one, two or three or four R^(2.1);        wherein nitrogen atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.2); wherein a carbon atom of the ring is optionally        substituted with one R^(2.3) or one R^(2.5); a nitrogen atom of        the ring is optionally substituted with one R^(2.4) or    -   R² and R⁴ are together with two adjacent carbon atoms of the        heteroaryl ring a 5- or 6-membered aryl or heteroaryl,        containing one, two or three heteroatoms independently selected        from among S, S(O), S(O)₂, O or N, wherein carbon atoms of the        ring are optionally and independently from each other        substituted with one, two or three R^(2.1); wherein nitrogen        atoms of the ring are optionally and independently from each        other substituted with one, two or three R^(2.2);    -   R^(2.1) is independently selected from among H, halogen, NC—,        O═, HO—, H-A-, H-A-C₁₋₆-alkylene-, R^(2.1.1)-A-, C₁₋₆-alkyl-A-,        C₃₋₈-cycloalkyl-A-, C₁₋₆-haloalkyl-A-,        R^(2.1.1)—C₁₋₆-alkylene-A-, C₁₋₆-alkyl-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,        C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-,        R^(2.1.1)—C₁₋₆-alkylene-A-C₁₋₆-alkylene-,        R^(2.1.1)-A-C₁₋₆-alkylene-, HO—C₁₋₆-alkylene-A-,        HO—C₁₋₆-alkylene-A-C₁₋₆-alkylene-, C₁₋₆-alkyl-O—C₁₋₆-alkylene-A-        and C₁₋₆-alkyl-O—C₁₋₆-alkylene-A-C₁₋₆-alkylene-        -   R^(2.1.1) is independently selected from among            -   aryl-; optionally substituted independently from each                other with one, two or three R^(2.1.1.1);            -   C₅₋₁₀-heteroaryl-; containing one, two, three or four                heteroatoms independently selected from among S, S(O),                S(O)₂, O and N, wherein carbon atoms of the ring are                optionally and independently from each other substituted                with one, two or three R^(2.1.1.1); wherein nitrogen                atoms of the ring are optionally and independently from                each other substituted with one, two or three                R^(2.1.1.2);            -   C₅₋₁₀-heterocyclyl-; containing one, two, three or four                heteroatoms independently selected from among S, S(O),                S(O)₂, O and N, wherein the ring is fully or partially                saturated, wherein carbon atoms of the ring are                optionally and independently from each other substituted                with one, two or three or four R^(2.1.1.1); wherein                nitrogen atoms of the ring are optionally and                independently from each other substituted with one, two                or three R^(2.1.1.2);            -   R^(2.1.1.1) is independently selected from among                halogen, HO—, O═, C₁₋₆-alkyl-, C₁₋₆-alkyl-O—,                C₁₋₆-haloalkyl-, C₁₋₆-haloalkyl-O— and C₃₋₈-cycloalkyl-;            -   R^(2.1.1.2) is independently selected from among O═,                C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,                C₁₋₆-alkyl-O—C₁₋₆-alkyl-, H(O)C—, C₁₋₆-alkyl-(O)C—,                tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-;    -   R^(2.2) is independently selected from among H-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-A-C₁₋₆-alkylene-,        C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,        C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-, R^(2.1.1)-A-C₁₋₆-alkylene-,        C₁₋₆-alkyl-S(O)₂— and C₁₋₆-alkyl-C(O)—, R^(2.1.1)-A-;    -   R^(2.3) and R⁴ are together selected from    -   among —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—,        —N(R^(2.3.1))C(O)—, —S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)₂—, R^(2.3),    -   R^(2.3), —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—,        —C(R^(2.3.2))₂—, —O—C(R^(2.3.2))₂—, —C(R^(2.3.2))₂N(R^(2.3.1))—,        —N(R^(2.3.1))C(R^(2.3.2))₂— and —C₁₋₄-alkylene-;        -   R^(2.3.1) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        -   R^(2.3.2) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;    -   R^(2.4) and R⁴ are together selected from    -   among —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—,        —S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—,        —S(O)₂—, —C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—,        —C(R^(2.4.2))₂N(R^(2.4.1))—, —N(R^(2.4.1))C(R^(2.4.2))₂—,        —C₁₋₄-alkylene-; and        -   R^(2.4.1) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;        -   R^(2.4.2) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;    -   R^(2.5) and R⁴ are together selected from among —C(R^(2.5.1))═,        ═C(R^(2.5.1))— and —N═; and        -   R^(2.5.1) is independently selected from among H,            C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,            HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,            H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene-,            (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;-   R³ is H or F;-   R⁴ is independently selected from among H, F, Cl, Br, phenyl-H₂C—O—,    HO—, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—,    C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,    (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-; preferably F, Cl, Br,    phenyl-H₂C—O—, HO—, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-,    C₁₋₆-alkyl-O—, C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,    C₁₋₆-alkyl-HN—C₁₋₄-alkylene- and (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-;-   A is a bond or independently selected from    -   among —O—, —S—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—,        —N(R⁵)S(O)₂—, —S(O)(═NR⁵)—N(R⁵)—, —N(R⁵)(NR⁵═)    -   S(O)—, —S(═NR⁵)₂—N(R⁵)—, —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C≡C—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O)₂—, —S(═NR⁵)—,        —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and        —N═(O)(R⁵)S—;-   R⁵ is independently selected from among H, C₁₋₆-alkyl- and NC—;-   or a salt thereof.

PREFERRED EMBODIMENTS

Preferred are the above compounds of formula 1, wherein R¹ is R^(1.a)and R^(1.a) is independently selected from among H, C₁₋₄-alkyl-, F, andHO—.

Preferred are the above compounds of formula 1, wherein R¹ is R^(1.b)and R^(1.b) is H.

Preferred are the above compounds of formula 1, wherein R¹ is R^(1.c)and two R^(1.c) are together —CH₂—.

Preferred are the above compounds of formula 1, wherein R² is R^(2.a)and R^(2.a) is R^(2.1).

Preferred are the above compounds of formula 1, wherein R² is R^(2.b)and R^(2.b) is R^(2.1.a).

Preferred are the above compounds of formula 1, wherein R² is R^(2.c)and R^(2.c) is aryl-; optionally substituted with one, two or threeresidues independently selected from R^(2.1); optionally substitutedwith one R^(2.3).

Preferred are the above compounds of formula 1, wherein R² is R^(2.d)and R^(2.d) is phenyl; optionally substituted with one, two or threeresidues independently selected from R^(2.1); optionally substitutedwith one R^(2.3).

Preferred are the above compounds of formula 1, wherein R² is R^(2.e)and R^(2.e) is C_(5 or 6)-heteroaryl-, containing one, two, three orfour heteroatoms independently selected from among S, S(O), S(O)₂, O andN, wherein carbon atoms of the ring are optionally and independentlyfrom each other substituted with one, two or three R^(2.1); whereinnitrogen atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.2); wherein a carbon atomof the ring is optionally substituted with one R^(2.3); a nitrogen atomof the ring is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.f)and R^(2.f) is bicyclic C₇₋₁₀-heteroaryl-, each containing one, two,three or four heteroatoms independently selected from S, S(O), S(O)₂, Oand N, wherein carbon atoms of the ring are optionally and independentlyfrom each other substituted with one, two or three R^(2.1); whereinnitrogen atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.2); wherein a carbon atomof the ring is optionally substituted with one R^(2.3); a nitrogen atomof the ring is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.g)and R^(2.g) is selected from

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1), wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.h)and R^(2.h) is selected from pyrazole, thiophene and furane, whereincarbon atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.1), wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.i)and R^(2.i) is selected from C₆-heterocyclyl- and C₇₋₁₀-heterocyclyl-,each containing one, two, three or four heteroatoms independentlyselected from among S, O and N and the ring is fully or partiallysaturated, wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.1); wherein nitrogen atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.2); wherein a carbon atom of the ring is optionally substitutedwith one R^(2.3) or one R^(2.5); a nitrogen atom of the ring isoptionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.j)and R^(2.j) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1), wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3) or one R^(2.5); anitrogen atom of the ring is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.k)and R^(2.k) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1), wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3) or one R^(2.5); anitrogen atom of the ring is optionally substituted with one R^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.1)and R^(2.1) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1), whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.m)and R^(2.m) is together with R⁴ and two adjacent carbon atoms of theheteroaryl ring a 5- or 6-membered aryl or heteroaryl, containing one,two or three heteroatoms independently selected from among S, S(O),S(O)₂, O and N, preferably pyrazole and naphtene, wherein carbon atomsof the ring are optionally and is independently from each othersubstituted with one, two or three R^(2.1), wherein possibly availablenitrogen atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.2).

Preferred are the above compounds of formula 1, wherein R² is R^(2.n)and R^(2.n) is from aryl-, pyrazole, thiophene and furane; whereincarbon atoms of the ring are optionally and independently from eachother substituted with one, two, three or four R^(2.1), wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4); or R^(2.n) is selectedfrom among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1), whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.o)and R^(2.o) is selected from among aryl-, pyrazole, thiophene andfurane; wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two, three or fourR^(2.1), wherein possibly available nitrogen atoms of the ring areoptionally and independently from each other substituted with R^(2.2);wherein a carbon atom of the ring is optionally substituted with oneR^(2.3); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R² is R^(2.p)and R^(2.p) is selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two, three or four R^(2.1), whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.2); wherein a carbonatom of the ring is optionally substituted with one R^(2.3) or oneR^(2.5); a nitrogen atom of the ring is optionally substituted with oneR^(2.4).

Preferred are the above compounds of formula 1, wherein R^(2.1) isR^(2.1.a) and R^(2.1.a) is selected from among H, halogen, NC—, O═, HO—,H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-,C₃₋₆-cycloalkyl-A-, C₁₋₄ haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from among

-   -   aryl-, optionally substituted independently from each other with        one, two or three residues independently selected from        R^(2.1.1.1);    -   C₅₋₁₀-heteroaryl-, containing one, two, three or four        heteroatoms selected independently from S, S(O), S(O)₂, O and N,        wherein carbon atoms of the ring are optionally and        independently from each other substituted with one, two or three        R^(2.1.1.1); wherein nitrogen atoms of the ring are optionally        and independently from each other substituted with one, two or        three R^(2.1.1.2);    -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four        heteroatoms selected independently from S, S(O), S(O)₂, O and N        and the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one, two or three R^(2.1.1.1); wherein        nitrogen atoms of the ring are optionally and independently from        each other substituted with one, two or three R^(2.1.12); and

-   R^(2.1.1.1) is independently selected from among halogen, HO—, O═,    C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O— and    C₃₋₆-cycloalkyl-; and

-   R^(2.1.1.2) is independently selected from among O═,    C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—,    C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and    tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R^(2.1.1) isR^(2.1.1.b) and R^(2.1.1.b) is phenyl or selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1.1.1), whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.1.1.2); and

-   R^(2.1.1.1) is independently selected from among halogen, HO—, O═,    C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O— and    C₃₋₆-cycloalkyl-; and-   R^(2.1.1.2) is independently selected from among O═, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—,    C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and    tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R^(2.1.1) isR^(2.1.1.c) and R^(2.1.1.c) is phenyl or selected from among

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1.1.1), whereinpossibly available nitrogen atoms of the ring are optionally andindependently from each other substituted with R^(2.1.1.2); and

-   R^(2.1.1.1) is independently selected from among F, Cl, Me, MeO— and    cyclopropyl-; and-   R^(2.1.1.2) is independently selected from among Me,    tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.

Preferred are the above compounds of formula 1, wherein R^(2.1.2) isR^(2.1.2.a) and R^(2.1.2.a) is selected from among H, NC—, C₁₋₄-alkyl-,C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene- and(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.1.2) isR^(2.1.2.b) and R^(2.1.2.b) is selected from among H, C₁₋₄-alkyl- andC₃₋₆-cycloalkyl-;

Preferred are the above compounds of formula 1, wherein R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected from amongH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂— and C₁₋₄-alkyl-C(O)—,R^(2.1.1)-A-;

Preferred are the above compounds of formula 1, wherein R^(2.2) isR^(2.2.b) and R^(2.2.b) is together with R⁴ selected from among —C(O)—,—S(O)—, —S(O)₂—, —C(R^(2.1.2))— and —C₁₋₄-alkylene-;

Preferred are the above compounds of formula 1, wherein R^(2.3) istogether with R⁴ a group R^(2.3.a) and R^(2.3.a) is selected from

among —O—, —S—, —N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—, —N(R^(2.3.1))C(O)—,—S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—, —C(O)O—, —OC(O)—, —C(O)—,—S(O)—, —S(O)₂—, —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—, —N═C—,—C(R^(2.3.2))₂—O—, —O—C(R^(2.3.2))₂—, —C(R^(2.3.2))₂N(R^(2.3.1))—,—N(R^(2.3.1))C(R^(2.3.2))₂— and —C₁₋₄-alkylene-; and

-   R^(2.3.1) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;-   R^(2.3.2) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.4) istogether with R⁴ a group R^(2.4.a) and R^(2.4.a) is selected from

among —N(R^(2.4.1))—, —C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—,—S(O)₂N(R^(2.4.1))—, —N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—, —S(O)₂—,—C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —N═C—, —C(R^(2.4.2))₂N(R^(2.4.1))—,—N(R^(2.4.1))C(R^(2.4.2))₂— and —C₁₋₄-alkylene-; and

-   R^(2.4.1) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;-   R^(2.4.2) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R^(2.5) istogether with R⁴ a group R^(2.5.a) and R^(2.5.a) is selected from among—C(R^(2.5.1))═, ═C(R^(2.5.1))— and —N═; and

-   R^(2.5.1) is independently selected from among H, C₁₋₄-alkyl-,    C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,    (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)N—C₁₋₄-alkylene-.

Preferred are the above compounds of formula 1, wherein R² is selectedfrom the Table 1R²—Embodiments of the invention for R², R^(2.1),R^(2.1.1), R^(2.2), R^(2.3), R^(2.4) and (if present):

TABLE 1 E # R² R^(2.1) R^(2.1.1) R^(2.2) R^(2.3-5) 1 R^(2.a) R^(2.1)R^(2.1.1.a) — 2 R^(2.a) R^(2.1) R^(2.1.1.b) — 3 R^(2.a) R^(2.1)R^(2.1.1.c) — 4 R^(2.b) R^(2.1.a) R^(2.1.1.a) — 5 R^(2.b) R^(2.1.a)R^(2.1.1.b) — 6 R^(2.b) R^(2.1.a) R^(2.1.1.c) — 7 R^(2.c) R^(2.1.a)R^(2.1.1.a) — — 8 R^(2.c) R^(2.1.a) R^(2.1.1.b) — — 9 R^(2.c) R^(2.1.a)R^(2.1.1.c) — — 10 R^(2.c) R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 11 R^(2.c)R^(2.1.a) R^(2.1.1.c) — R^(2. 4.a) 12 R^(2.c) R^(2.1.a) R^(2.1.1.c) —R^(2. 5.a) 13 R^(2.d) R^(2.1.a) R^(2.1.1.a) — — 14 R^(2.d) R^(2.1.a)R^(2.1.1.b) — — 15 R^(2.d) R^(2.1.a) R^(2.1.1.c) — — 16 R^(2.d)R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 17 R^(2.d) R^(2.1.a) R^(2.1.1.c) —R^(2. 4.a) 18 R^(2.d) R^(2.1.a) R^(2.1.1.c) — R^(2. 5.a) 19 R^(2.e)R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 20 R^(2.e) R^(2.1.a) R^(2.1.1.b)R^(2.2.a) — 21 R^(2.e) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 22 R^(2.f)R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 23 R^(2.f) R^(2.1.a) R^(2.1.1.b)R^(2.2.a) — 24 R^(2.f) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 25 R^(2.g)R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 26 R^(2.g) R^(2.1.a) R^(2.1.1.b)R^(2.2.a) — 27 R^(2.g) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 28 R^(2.h)R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 29 R^(2.h) R^(2.1.a) R^(2.1.1.b)R^(2.2.a) — 30 R^(2.h) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 31 R^(2.e)R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 32 R^(2.e) R^(2.1.a) R^(2.1.1.c) —R^(2. 4.a) 33 R^(2.e) R^(2.1.a) R^(2.1.1.c) — R^(2. 5.a) 34 R^(2.g)R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 35 R^(2.g) R^(2.1.a) R^(2.1.1.c) —R^(2. 4.a) 36 R^(2.g) R^(2.1.a) R^(2.1.1.c) — R^(2. 5.a) 37 R^(2.h)R^(2.1.a) R^(2.1.1.c) — R^(2.3.a) 38 R^(2.h) R^(2.1.a) R^(2.1.1.c) —R^(2. 4.a) 39 R^(2.h) R^(2.1.a) R^(2.1.1.c) — R^(2. 5.a) 40 R^(2.i)R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 41 R^(2.i) R^(2.1.a) R^(2.1.1.b)R^(2.2.a) — 42 R^(2.i) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 43 R^(2.j)R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 44 R^(2.j) R^(2.1.a) R^(2.1.1.b)R^(2.2.a) — 45 R^(2.j) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 46 R^(2.k)R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 47 R^(2.k) R^(2.1.a) R^(2.1.1.b)R^(2.2.a) — 48 R^(2.k) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) — 49 R^(2.l)R^(2.1.a) R^(2.1.1.a) R^(2.2.a) — 50 R^(2.l) R^(2.1.a) R^(2.1.1.b)R^(2.2.a) — 51 R^(2.l) R^(2.1.a) R^(2.1.1.c) R^(2.2.a) —

For a better understanding of the Table 1R²—Embodiments of the inventionexample (E#) 21, can also be read as a group R², wherein

-   R² is R^(2.e) and R^(2.e) is C_(5 or 6)-heteroaryl-, containing one,    two, three or four heteroatoms independently selected from among S,    S(O), S(O)₂, O and N, wherein carbon atoms of the ring are    optionally and independently from each other substituted with one,    two or three R^(2.1); wherein nitrogen atoms of the ring are    optionally and independently from each other substituted with one,    two or three R^(2.2); and    -   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from among H,        halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,        C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,        R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,        —C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,        C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,        R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,        R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,        HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-        and C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and        -   R^(2.1.1) is R^(2.1.1.c) and R^(2.1.1.c) is phenyl or            selected from among

-   -   -   -   wherein carbon atoms of the ring are optionally and                independently from each other substituted with one, two                or three R^(2.1.1.1), wherein possibly available                nitrogen atoms of the ring are optionally and                independently from each other substituted with                R^(2.1.1.2); and            -   R^(2.1.1.1) is independently selected from among F, Cl,                Me, MeO— and cyclopropyl-; and            -   R^(2.1.1.2) is independently selected from among Me,                tetrahydrofuranylmethyl- and tetrahydropyranylmethyl;                and

    -   R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected        from among H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,        C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,        C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— and R^(2.1.1)-A-.

Preferred are the above compounds of formula 1, wherein R³ is R^(3.a)and R^(3.a) is H.

Preferred are the above compounds of formula 1, wherein R³ is R^(3.b)and R^(3.b) is F.

Preferred are the above compounds of formula 1, wherein R⁴ is R^(4.a)and R^(4.a) is H, F, Cl, Br, phenyl-H₂C—O—, HO—, C₁₋₄-alkyl-,C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O— and C₁₋₄-haloalkyl-O—.

Preferred are the above compounds of formula 1, wherein R⁴ is R^(4.b)and R^(4.b) is H or F.

Preferred are the above compounds of formula 1, wherein R⁴ is R^(4.c)and R^(4.c) is F; preferably in is ortho position.

Preferred are the above compounds of formula 1, wherein A is A^(a) andA^(a) is a bond or independently selected from among —O—, —C(O)N(R⁵)—,—N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—, —C(O)O—, —OC(O)—, —C(O)—,—S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and —N═(O)(R⁵)S— and R⁵ is R^(5.a)and R^(5.a) is in dependently selected from among H, C₁₋₄-alkyl-, NC—.

Preferred are the above compounds of formula 1, wherein A is A^(b) andA^(b) is a bond.

Preferred are the above compounds of formula 1, wherein X is X^(a) andX^(a) is S or O; preferably S; and Y is Y^(a) and Y^(a) is CH;

Preferred are the above compounds of formula 1, wherein X is X^(b) andX^(b) is S; and Y is Y^(b) and Y^(b) is N;

Preferred are the above compounds of formula 1, wherein R² is R^(2q) andR^(2q) is selected from among formulas (b1) to (g1),

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein nitrogenatoms of the ring are optionally and independently from each othersubstituted with one, two or three R^(2.2),

-   wherein-   R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from among H,    halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,    C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,    R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,    C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,    R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,    R^(2.1.1)-A-C₁₋₄-alkylene-, HO—C₁₋₄-alkylene-A-,    HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- and    C₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and    -   R^(2.1.1) is R^(2.1.1.a) and R^(2.1.1.a) selected from among        -   aryl-, optionally substituted independently from each other            with one, two or three is residues independently selected            from R^(2.1.1.1);        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2);        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from among halogen, HO—,        O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl- and        C₁₋₄-haloalkyl-O—, C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from among O═,        C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,        tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and

R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected from amongH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-.

Particularly preferred are the above compounds of formula 1, wherein R²is selected R^(2.r) and R^(2.r) is selected from among formulas (b1) to(g1),

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one or two F, —CN, —SO₂Me, ═O, —COMe and—SO2-pyrazinyl-Me, wherein nitrogen atoms of the is ring are optionallyand independently from each other substituted with Me, Et and—CH₂-tetrahydropyranyl.

Preferred are the above compounds of formula 1, wherein R³ is H.

Preferred are the above compounds of formula 1, wherein R³ is F.

Preferred are the above compounds of formula 1, wherein R⁴ is R^(4.d),wherein R^(4.d) is selected from among H, F, Cl and Br.

Particularly preferred are the above compounds of formula 1, wherein R⁴is R^(4.e), wherein R^(4.d) is H or Br, preferably H.

Particularly preferred are the above compounds of formula 1, wherein R⁴is R^(4.e), wherein R^(4.d) is H or F,

Preferred are the above compounds of formula 1, wherein

R² and R⁴ are together with two adjacent carbon atoms of the heteroarylring a 5- or 6-membered aryl, preferably phenyl ring, wherein

the 5- or 6-membered aryl is optionally substituted by one or two,preferably one, residue selected from among

-   -   halogen, —CN,        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from among S, S(O),            S(O)₂, O and N, wherein carbon atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.1); wherein nitrogen atoms            of the ring are optionally and independently from each other            substituted with one, two or three R^(2.1.1.2); and        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O or            N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from among halogen, HO—,        O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,        C₁₋₄-haloalkyl-O—, C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from among O═,        C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—, is        tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.

Particularly preferred are the above compounds of formula 1, wherein

R² and R⁴ are together with two adjacent carbon atoms of the heteroarylring a 5- or 6-membered aryl, preferably phenyl ring, wherein the 5- or6-membered aryl is optionally substituted by one or two, preferably one,residue selected from among

Br, F, —CN, phenyl and a group of formula (a1).

Preferred is a compound of formula 1, wherein

R¹ is H,

R² is R^(2.q) or R^(2r), R³ is H or F, and

R⁴ is R^(4.d) or R^(4.e),

or salts thereof.

Preferred is a compound of formula 1, wherein

R¹ is H,

R³ is H or F, and

R² and R⁴ are together with two adjacent carbon atoms of the heteroarylring a 5- or 6-membered aryl, preferably phenyl ring, wherein

the 5- or 6-membered aryl is optionally substituted by one or two,preferably one, residue selected from among

-   -   halogen, —CN,        -   C₅₋₁₀-heteroaryl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N, wherein carbon atoms of the ring are optionally and            independently from each other substituted with one, two or            three R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and        -   C₅₋₁₀-heterocyclyl-, containing one, two, three or four            heteroatoms selected independently from S, S(O), S(O)₂, O            and N and the ring is fully or partially saturated, wherein            carbon atoms of the ring are optionally and independently            from each other substituted with one, two or three            R^(2.1.1.1); wherein nitrogen atoms of the ring are            optionally and independently from each other substituted            with one, two or three R^(2.1.1.2); and    -   R^(2.1.1.1) is independently selected from among halogen, HO—,        O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,        C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and    -   R^(2.1.1.2) is independently selected from among O═,        C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,        C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,        tetrahydrofuranylmethyl- and tetrahydropyranylmethyl,

or salts thereof.

Preferred is a compound of formula 1, wherein

R¹ is H,

R³ is H or F, and

R² and R⁴ are together with two adjacent carbon atoms of the heteroarylring a 5- or 6-membered aryl, preferably phenyl ring, wherein the 5- or6-membered aryl is optionally substituted by one or two, preferably one,residue selected from among

Br, F, —CN, phenyl and a group of formula (a1).

or salts thereof.

Preferred is a compound of formula 1, wherein

-   X is selected from among S and O;-   Y is selected from among N and CH;-   R¹ is independently selected from among H, C₁₋₄-alkyl-, halogen,    HO—, C₁₋₄-alkyl-O—, H₂N—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂N— and    C₁₋₆-alkyl-C(O)HN—;-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably is examples (E#) 7-51, preferably one of the    groups selected from among 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,    18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,    34, 35, 36, 37, 38, 39 or 40, 41, 42, 43, 44, 45, 45, 46, 47, 48,    49, 50 and 51;-   R³ is H or F;-   R⁴ is independently selected from among H, F, Cl, Br, phenyl-H₂C—O—,    HO—, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-, C₁₋₆-alkyl-O—,    C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,    C₁₋₆-alkyl-HN—C₁₋₄-alkylene- and (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-;-   A is a bond or independently selected from    -   among —O—, —S—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—,        —N(R⁵)S(O)₂—, —S(O)(═NR⁵)—N(R⁵)—, —N(R⁵)(NR⁵═)    -   S(O)—, —S(═NR⁵)₂—N(R⁵)—, —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C≡C—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)—,    -   S(O)₂—, —S(═NR⁵)—, —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—,        —(R⁵N═)(O)S— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from among H, C₁₋₆-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   X is selected from among S and O;-   Y is selected from among N and CH;-   R¹ is R^(1.a) and R^(1.a) is independently selected from among H,    C₁₋₄-alkyl-, F and HO—.-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably is examples (E#) 7-51, preferably one of the    groups selected from among 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,    18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,    34, 35, 36, 37, 38, 39 or 40, 41, 42, 43, 44, 45, 45, 46, 47, 48,    49, 50, 51;-   R³ is H or F;-   R⁴ is R^(4.a) and R^(4.a) is H, F, Cl, Br, phenyl-H₂C—O—, HO—,    C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O— and    C₁₋₄-haloalkyl-O—;-   A is a bond or independently selected from    -   among —O—, —S—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—,        —N(R⁵)S(O)₂—, —S(O)(═NR⁵)—N(R⁵)—, —N(R⁵)(NR⁵═)    -   S(O)—, —S(═NR⁵)₂—N(R⁵)—, —N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C≡C—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)—,    -   S(O)₂—, —S(═NR⁵)—, —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—,        —(R⁵N═)(O)S— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from among H, C₁₋₆-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   X is selected from among S and O;-   Y is selected from among N and CH;-   R¹ is R^(1.a) and R^(1.a) is independently selected from among H,    C₁₋₄-alkyl-, F and HO—.-   or two R¹ are together C₁₋₄-alkylene;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from among 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28,    29, 30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47, 48;-   R³ is H or F;-   R⁴ is R^(4a) and R^(4a) is H, F, Cl, Br, phenyl-H₂C—O—, HO—,    C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-O— and,    C₁₋₄-haloalkyl-O—;-   A is A^(a) and A^(a) is a bond or independently selected from    -   among —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and        —N═(O)(R⁵)S—;-   R⁵ is R^(5.a) and R^(5.a) is independently selected from among H,    C₁₋₄-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   X is selected from among S and O;-   Y is selected from among N and CH;-   R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from among 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28,    29, 30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47, 48;-   R³ is H or F;-   R⁴ is R^(4.b) and R^(4.b) is H or F;-   A is A^(a) and A^(a) is a bond or independently selected from among    —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—, —C(O)O—,    —OC(O)—, —C(O)—, S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and,    —N═(O)(R⁵)S—;-   R⁵ is R^(5.a) and R^(5.a) is independently selected from among H,    C₁₋₄-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   X is selected from among S and O;-   Y is selected from among N and CH;-   R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;-   R² is selected of the examples of the Table 1R²—Embodiments of the    invention; preferably examples (E#) 7-51, preferably one of the    groups selected from among 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28,    29, 30, 34, 35, 36, 37, 38, 39 or 43, 44, 45, 46, 47, 48;-   R³ is H or F;-   R⁴ is R^(4.b) and R^(4.b) is H or F;-   A is A^(a) and A^(a) is a bond or independently selected from    -   among —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and        —N═(O)(R⁵)S—;-   R⁵ is R^(5.a) and R^(5.a) is independently selected from among H,    C₁₋₄-alkyl- and NC—;-   or a salt thereof.

Preferred is a compound of formula 1, wherein

-   X is selected from among S and O;-   Y is selected from among N and CH;-   R¹ is R^(1.b) and R^(1.b) is H; or two R¹ are together —CH₂—;-   R² is selected from among    -   R^(2.1);    -   phenyl-; optionally substituted with one or two residues        independently selected from R^(2.1); optionally substituted with        one R^(2.3);    -   C₅-heteroaryl-; containing two or three independently selected        from among S, O and N, wherein carbon atoms of the ring are        optionally and independently from each other substituted with        one R^(2.1); wherein nitrogen atoms of the ring are optionally        and is independently from each other substituted with one        R^(2.2);    -   monocyclic C₆-heterocyclyl containing one or two nitrogen atoms,        wherein the ring is fully or partially saturated, wherein carbon        atoms of the ring are optionally and independently from each        other substituted with one R^(2.1); wherein nitrogen atoms of        the ring are optionally and independently from each other        substituted with one R^(2.2);    -   bicyclic C_(9 or 10)-heterocyclyl-; containing one, two, three        or four heteroatoms independently selected from among S(O)₂, O        and N, wherein the ring is fully or partially saturated, wherein        carbon atoms of the ring are optionally and independently from        each other substituted with one, two or three R^(2.1); wherein        nitrogen atoms of the ring are optionally and independently from        each other substituted with one R^(2.2);    -   R^(2.1) is independently selected from among halogen, NC—, O═,        H-A-, H-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,        R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,        HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; preferably F, NC—, O═, H-A-,        H-A-CH₂—, R^(2.1.1)-A-, H₃C-A-, H₃C—CH₂-A-, Cyclopropyl-A-,        R^(2.1.1)—CH₂—CH₂-A-, R^(2.1.1)—CH₂-A-, H₃C-A-CH₂—CH₂— and        HO—C₄-alkylene-A-CH₂—;        -   R^(2.1.1) is independently selected from among            -   phenyl-;            -   C_(5 or 6)-heterocyclyl-; containing one or two                heteroatoms independently selected from among O and N,                wherein the ring is fully or partially saturated,                wherein nitrogen atoms of the ring are optionally and                independently from each other substituted with one                C₁₋₄-alkyl-; preferably H₃C—;    -   R^(2.2) is independently selected from among H-A-C₁₋₄-alkylene-,        C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,        R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-C(O)—; preferably        H-A-CH₂—, H-A-CH₂—CH₂—, cyclopropyl-, H₃C-A-CH₂—CH₂—,        R^(2.1.1)-A-CH₂— and H₃C—C(O)—;    -   R^(2.3) and R⁴ are together a group selected from    -   among —N(R^(2.3.1))—, —C(O)N(R^(2.3.2))— and —N(R^(2.3.1))C(O)—;        -   R^(2.3.1) is independently selected from among H and H₃C—;-   R³ is H or F;-   R⁴ is R^(4.b) and R^(4.b) is H or F;-   A is a bond or independently selected from    -   among —O—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,        —C(O)O—, —OC(O)—, —C(O)—, —S(O)₂— and —N═(O)(R⁵)S—;-   R⁵ is independently selected from among H and C₁₋₄-alkyl-;-   or a salt thereof.

Preferred are the above compounds of formula 1, in its enantiomericallypure form of formula 1′

-   wherein X, Y, R¹, R², R³ and R⁴ have the above mentioned meaning.

USED TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms.

In general in single groups like HO, H₂N, S(O), S(O)₂, NC (cyano), HOOC,F₃C or the like, the skilled artisan can see the radical attachmentpoint(s) to the molecule from the free valences of the group itself. Forcombined groups comprising two or more subgroups, the last namedsubgroup is the radical attachment point, for example, the substituent“aryl-C₁₋₄-alkyl-” means an aryl group which is bound to aC₁₋₄-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail. An asterisk is may be used in sub-formulas to indicatethe bond which is connected to the core molecule as defined.

Many of the followings terms may be used repeatedly in the definition ofa formula or group and in each case have one of the meanings givenabove, independently of one another.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

The expressions “prevention”, “prophylaxis”, “prophylactic treatment” or“preventive treatment” used herein should be understood synonymous andin the sense that the risk to develop a condition mentioned hereinbeforeis reduced, especially in a patient having elevated risk for saidconditions or a corresponding anamnesis, e.g. elevated risk ofdeveloping metabolic disorder such as diabetes or obesity or anotherdisorder mentioned herein. Thus the expression “prevention of a disease”as used herein means the management and care of an individual at risk ofdeveloping the disease prior to the clinical onset of the disease. Thepurpose of prevention is to combat the development of the disease,condition or disorder, and includes the administration of the activecompounds to prevent or delay the onset of the symptoms or complicationsand to prevent or delay the development of related diseases, conditionsor disorders. Success of said preventive treatment is reflectedstatistically by reduced incidence of said condition within a patientpopulation at risk for this condition in comparison to an equivalentpatient population without preventive treatment.

The expression “treatment” or “therapy” means therapeutic treatment ofpatients having already developed one or more of said conditions inmanifest, acute or chronic form, including symptomatic treatment inorder to relieve symptoms of the specific indication or causal treatmentin order to reverse or partially reverse the condition or to delay theprogression of the indication as far as this may be possible, dependingon the condition and the severity thereof. Thus the expression“treatment of a disease” as used herein means the management and care ofa patient having developed the disease, condition or disorder. Thepurpose of treatment is to combat the disease, condition or disorder.Treatment includes the administration of the active compounds toeliminate or control the disease, condition or disorder as well as toalleviate the symptoms or complications associated with the disease,condition or disorder.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

As used herein the term “prodrug” refers to (i) an inactive form of adrug that exerts its effects after metabolic processes within the bodyconverting it to a usable or active form, or (ii) a substance that givesrise to a pharmacologically active metabolite, although not itselfactive (i.e. an inactive precursor).

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative, carrier or precursor of the parent compound or active drugsubstance which undergoes at least some biotransformation prior toexhibiting its pharmacological effect(s). Such prodrugs either havemetabolically cleavable or otherwise convertible groups and are rapidlytransformed in vivo to yield the parent compound, for example, byhydrolysis in blood or by activation via oxidation as in case ofthioether groups. Most common prodrugs include esters and amide analogsof the parent compounds. The prodrug is formulated with the objectivesof improved chemical stability, improved patient acceptance andcompliance, improved bioavailability, prolonged duration of action,improved organ selectivity, improved formulation (e.g., increasedhydrosolubility), and/or decreased side effects (e.g., toxicity). Ingeneral, prodrugs themselves have weak or no biological activity and arestable under ordinary conditions. Prodrugs can be readily prepared fromthe parent compounds using methods known in the art, such as thosedescribed in A Textbook of Drug Design and Development,Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, isparticularly Chapter 5: “Design and Applications of Prodrugs”; Design ofProdrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical andOcular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods inEnzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985,particularly pp. 309-396; Burger's Medicinal Chemistry and DrugDiscovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995,particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as NovelDelivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,1987, each of which is incorporated herein by reference in theirentireties.

The term “pharmaceutically acceptable prodrug” as used herein means aprodrug of a compound of the invention which is, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include salts from ammonia, L-arginine, betaine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine,1H-imidazole, lysine, magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2′, 2″-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid,2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid,2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formicacid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonicacid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid,hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine,maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid,methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionicacid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid. Further pharmaceutically acceptable salts can beformed with cations from metals like aluminium, calcium, lithium,magnesium, potassium, sodium, zinc and the like. (also seePharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66,1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts,) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer selected from among 2,3, 4, 5 or 6, either alone or in combination with another radicaldenotes an acyclic, saturated, branched or linear hydrocarbon radicalwith 1 to n C atoms. For example the term C₁₋₅-alkyl embraces theradicals H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—,H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer selected from 2, 3,4, 5 or 6, preferably 4 or 6, either alone or in combination withanother radical, denotes an acyclic, straight or branched chain divalentalkyl radical containing from 1 to n carbon atoms. For example the termC₁₋₄-alkylene includes —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—,—C(CH₃)₂—, —CH(CH₂CH₃)—, —CH(CH₃)—C H₂—, —CH₂—CH(CH₃)—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH(CH₃)—, —CH(CH₃)—CH₂—CH₂—,—CH₂—CH(CH₃)—CH₂—, —CH₂—C(CH₃)₂—, —C(CH₃)₂—CH₂—, —CH(CH₃)—CH(CH₃)—,—CH₂—CH(CH₂CH₃)—, —CH(CH₂CH₃)—CH₂—, —CH(CH₂CH₂CH₃)—, —CH(CH(CH₃))₂— and—C(CH₃)(CH₂CH₃)—.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer selected from 4,5, 6, 7 or 8, preferably 4, 5 or 6, either alone or in combination withanother radical denotes a cyclic, saturated, unbranched hydrocarbonradical with 3 to 8 C atoms. For example the term C₃₋₈-cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl.

By the term “halo” added to a “alkyl”, “alkylene” or “cycloalkyl” group(saturated or unsaturated) is such a alkyl or cycloalkyl group whereinone or more hydrogen atoms are replaced by a halogen atom selected fromamong fluorine, chlorine or bromine, preferably fluorine and chlorine,particularly preferred is fluorine. Examples include: H₂FC—, HF₂C—,F₃C—.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second five-or six-membered, carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl.

The term “C₅₋₁₀-heterocyclyl” means a saturated or unsaturated mono- orpolycyclic-ring systems including aromatic ring system containing one ormore heteroatoms independently selected from N, O or S(O)_(r), whereinr=0, 1 or 2, consisting of 5 to 10 ring atoms wherein none of theheteroatoms is part of the aromatic ring. The term “heterocyclyl” isintended to include all the possible isomeric forms. Thus, the term“heterocyclyl” includes the following exemplary structures which are notdepicted as radicals as each form may be attached through a covalent(single or double) bond to any atom so long as appropriate valences aremaintained:

The term “C₅₋₁₀-heteroaryl” means a mono- or polycyclic-ring systemscontaining one or more heteroatoms independently selected from N, O andS(O)_(r), wherein r=0, 1 or 2, consisting of 5 to 10 ring atoms whereinat least one of the heteroatoms is part of aromatic ring. The term“heteroaryl” is intended to include all the possible isomeric forms.Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

Preparation

General Synthetic Methods

The invention also provides processes for making a compound of FormulaI. In all methods, unless specified otherwise, R¹, R² and n in theformulas below shall have the meaning of R¹, R² and n in Formula I ofthe invention described herein above.

Optimal reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by thin layer chromatography (TLC) or LC-MS, ifdesired, and intermediates and products may be purified bychromatography on silica gel, HPLC and/or by recrystallization. Theexamples which follow are illustrative and, as recognized by one skilledin the art, particular reagents or conditions could be modified asneeded for individual compounds without undue experimentation. Startingmaterials and intermediates used, in the methods below, are eithercommercially available or easily prepared from commercially availablematerials by those skilled in the art.

A compound of Formula V, VII and IX may be made by the method outlinedin Scheme 1:

As illustrated in Scheme 1, a compound of Formula II, wherein PGrepresents a protecting group (e.g. tert-butoxycarbonyl), may be reactedwith an aqueous ammonia solution, using standard literature proceduresfor the formation of an amide. For example, in the presence of a basesuch as N-methyl-morpholine or N-ethyl-morpholine and an activatingagent such as O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate(TBTU). The reaction is conveniently carried out in a suitable solventsuch as N,N-dimethylformamide. Standard peptide coupling reactions knownin the art (see for example M. Bodanszky, 1984, The Practice of PeptideSynthesis, Springer-Verlag) may be employed in these syntheses.

Dehydration of an amide such as in a compound of Formula III or FormulaIX to the corresponding nitrile of Formula IV or VII may be carried outby use of a dehydration agent such as (methoxycarbonylsulfamoyl)triethylammonium hydroxide, in a suitable solvent such as dichloromethane (DCM).

Reacting an acid of Formula VI using standard literature procedures forthe formation of an amide, for example in the presence of a base such asN,N-diisopropylethylamine (DIPEA) and an activating agent such as HATUor TBTU, with an amine of Formula V or VIII in a suitable solvent, isprovides a compound of Formula VII or IX. Standard peptide couplingreactions known in the art (see for example M. Bodanszky, 1984, ThePractice of Peptide Synthesis, Springer-Verlag) may be employed in thesesyntheses.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Synthesis’, T. W. Greene and P. G. M.Wuts, Wiley-Interscience. For example, for the deprotection oftert-butoxycarbonyl, an acid such as formic acid, trifluoroacetic acid,p-toluenesulfonic acid or HCl may be used in a suitable solvent such aswater, DCM or dioxane. Another method to deprotect tert-butoxycarbonylis the reaction with trimethyliodosilane or trimethylchlorosilane incombination with sodium iodide in an appropriate solvent likeacetonitrile, DMF or DCM.

As illustrated in Scheme 2, (transition) metal catalyzed reaction of acompound of Formula VII or IX wherein L is I, Br or Cl, provides acompound of Formula X or XI. For example, reaction with a boronic acidor the corresponding boronic acid ester, in a suitable solvent such asacetonitrile, in the presence of a suitable catalyst such as1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and asuitable base such as K₂CO₃ provides a compound of Formula X or XI.Alternatively, reaction of a compound of Formula VII or IX, wherein L isI, Br or Cl with a tributyl(vinyl)tin reagent in the presence of asuitable catalyst such as bis-(triphenylphosphin)-palladiumchloride, ina suitable solvent such as dimethylformamide (DMF) and if desirable inthe presence of an additive such as tetraethylammonium chloride providescompounds of Formula X or XI. Further, reaction of a compound of FormulaVII or IX, wherein L is I or Br, may be reacted with an amine in thepresence of a suitable catalyst such as Cu(I)I and a suitable base suchas caesium carbonate and a suitable promotor such as L-proline providesa compound of Formula X or XI.

In an inversed fashion compounds of formula VII or IX (L: I, Br, Cl) canbe converted into the corresponding boronic acid derivatives VIIa orIXa, wherein R can be H or lower alkyl independently and the residues Rcan form a ring. For example, VII or IX can be reacted withbis-pinacolato-diboron in the presence of a suitable catalyst such as1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and asuitable base such as potassium acetate or sodium, potassium or cesiumcarbonate or phosphate, in a suitable solvent such as dioxan,dimethylformamide (DMF), or dichloromethane (DCM) to yield the boronicesters VIIa or IXa, respectively. These can be reacted with appropriatearomatic halides in analogy as above to yield the desired couplingproducts of formula X or XI.

Further modifications of compounds of Formula X, XI and I by methodsknown in the art and illustrated in the Examples below, may be used toprepare additional compounds of the invention.

Dehydration of an amide of Formula XI to the corresponding nitrile ofFormula X may be carried out by use of a dehydration agent such as(methoxycarbonylsulfamoyl)triethyl ammonium hydroxide, in a suitablesolvent such as DCM.

As illustrated in Scheme 3, (transition) metal catalyzed reaction of acompound of Formula IV wherein X is I, Br or Cl, provides a compound ofFormula XII. For example, reaction with a boronic acid or thecorresponding boronic acid ester, in a suitable solvent such asacetonitrile, in the presence of a suitable catalyst such as1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride and asuitable base such as K₂CO₃ provides a compound of Formula XII.

An acid of Formula VI using standard literature procedures for theformation of an amide, for example in the presence of a base such asDIPEA and an activating agent such as HATU or TBTU, can be reacted withan amine of Formula XII in a suitable solvent. Standard peptide couplingreactions known in the art (see for example M. Bodanszky, 1984, ThePractice of Peptide Synthesis, Springer-Verlag) may be employed in thesesyntheses. Deprotection of functional groups is described in ‘ProtectiveGroups in Organic Synthesis’, T. W. Greene and P. G. M. Wuts, isWiley-Interscience. For example, for the deprotection oftert-butoxycarbonyl, an acid such as formic acid, p-toluenesulfonicacid, trifluoroacetic acid or HCl may be used in a suitable solvent suchas water, DCM or dioxane and can be performed on the crude amidecoupling product to provide a compound of Formula I. Another method todeprotect tert-butoxycarbonyl is the reaction with trimethyliodosilaneor trimethylchlorosilane in combination with sodium iodide in anappropriate solvent like acetonitrile, DMF or DCM.

As illustrated in Scheme 4, amino nitrile derivatives of Formula XIIIcan be converted to substituted amino nitriles of Formula V viaalkylation to compounds of Formula XIV, followed by deprotection of theamino group. During the alkylation step a suitable base is used in anappropriate solvent, using a benzylation agent XV with an appropriateleaving group like Cl, Br, or sulfonates. Especially useful is the useof sodium hydroxide as base in water and DCM under phase transferconditions using benzyltrimethylammonium chloride as described forexample by Naidu et al, WO2011/46873. The protective group is removedunder acidic conditions, e.g. aq. HCl in dioxan. The amino nitrile V isfurther processed as depicted in Scheme 1.

As illustrated in Scheme 5, heteroaromatic aldehydes of type XV can beconverted to dehydroamino acid derivatives of formula XVII by use ofphosphono glycine derivatives of type XVI. This is performed in thepresence of a base e.g., not restricted to tetramethylguanidine, inaprotic solvents like THF. This procedure is published for analogousexamples in Cartier et al, J. Org. Chem., 2002, 67, 6256-6259.

The coupling of derivatives of formula XVII with L=I, Br or Cl withboronic acid derivatives to compounds of general formula XVIII isperformed in the same way as depicted in Scheme 2 during the conversionof compounds VII to compounds X, or of compounds I× to compounds XI,respectively.

As described e.g. in Cartier et al, J. Org. Chem., 2002, 67, 6256-6259with an anaologous system, conversion of dehydroamino acid derivativesof formula XVIII to chiral amino acid derivatives XIX can be performedby homogenous catalytic hydrogenation using a chiral catalyst.Especially useful is(+)-1,2-bis-((2S,5S)-2,5-diethylphospholano)-benzene-(cyclooctadiene)-rhodium(I) trifluoromethanesulfonate, which delivers the desired (2S)-aminoacid derivative XIX in a solvent like methanol or ethanol for example atroom temperature and 50 psi. A useful amount of the catalyst is 0.1equivalents, but might be less than that.

The hydrolysis of ester derivatives like XIX to acids of general formulaXX can be performed in alkaline media, however, under careful conditionsnot to epimerize the stereo center adjacent to the ester function.Appropriate conditions are lithium hydroxide in methanol/water (about 10mmol in 50 mL solvent and 90 min at room temperature. The amino acid isset free carefully with weak acids (e.g. 2 N acetic acid) not to cleavethe acid labile Boc protective group.

The conversion of acid derivatives XX to primary amides XXI andfollowing Boc deprotection to primary amides of formula XXI proceeds inan analogous fashion to the conversion of compound II to compounds VIIIvia compound III as depicted in Scheme I. Amide coupling of amines ofthe formula XXI with protected amino acids VI leads to amides of thegeneral formula (2S)-XI in analogy to the formation of amides IX asdepicted in Scheme 1. Compounds of the formula (2S)-XI are converted tothe target compounds (2S)-I in the same way as described in Scheme 2.

Synthetic Examples

The following are representative compounds of the invention which can bemade by the general synthetic schemes, the examples, and known methodsin the art. Starting materials and intermediates were eithercommercially available and purchased from catalogues of ABCR, ACROS,ACTIVATE, ALDRICH, ALFA, ANISYN, APOLLO, CHEM IMPEX, COMBI-BLOCKS,E-MERCK, FLUKA, GOLDENBRIDGE, MILESTONES, PEPTECH, PHARMABRIDGE,SPECBIOCHEM or were synthesized according to literature or as describedbelow in “Synthesis of starting materials/educts” Liquidchromatography-mass spectroscopy (LCMS) retention time and observed m/zdata for the compounds below are obtained by one of the followingmethods:

LC-MS Method V001_003 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA][Methanol] [ml/min] [°0 C.] 0.0 95 5 4 60 0.20 95 5 4 60 1.5 0 100 4 601.75 0 100 4 60

LC-MS Method V001_004 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA][Methanol] [ml/min] [°0 C.] 0.0 95 5 4 60 0.20 95 5 4 60 1.5 0 100 4 601.9 0 100 4 60 2.0 95 5 4 60

LC-MS Method V001_007 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H2O, 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 4 60 1.6 0 100 4 60 1.85 0 100 4 601.9 95 5 4 60

LC-MS Method V003_003 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% NH₃][Methanol] [ml/min] [° C.] 0.0 95 5 4 60 0.2 95 5 4 60 1.5 0 100 4 601.75 0 100 4 60

LC-MS Method V011_S01 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H₂O, 0.1% NH₃][Acetonitril] [ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 601.7 0 100 5 60

LC-MS Method V012_S01 Device-Description Waters Alliance with DAD andMSD Column Waters XBridge C18 Column Dimension 4.6 × 30 mm Particle Size3.5 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H₂O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 601.7 0 100 5 60

LC-MS Method X001_004 Device-Description Waters Acquity with DAD and MSDColumn Waters XBridge C18 Column Dimension 2.1 × 20 mm Particle Size 2.5μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.10% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 1.4 60 0.05 95 5 1.4 60 1.00 0 1001.4 60 1.1 0 100 1.4 60

LC-MS Method X012_S01 Device-Description Waters Acquity with DAD and MSDColumn Waters XBridge BEH C18 Column Dimension 2.1 × 30 mm Particle Size1.7 μm Solvent Gradient % Sol % Sol Flow Temp time [min] [H₂O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0100 1.6 60 1.10 0 100 1.6 60

LC-MS Method X018_S01 Device-Description Waters Acquity with DAD and MSDColumn Waters Sunfire C18 Column Dimension 2.1 × 30 mm Particle Size 2.5μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0100 1.5 60 1.10 0 100 1.5 60

LC-MS Method Z001_002 Device-Description Agilent 1200 with DAD and MSDColumn Waters XBridge C18 Column Dimension 3 × 30 mm Particle Size 2.5μm Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 1002.2 60 1.80 0 100 2.2 60

Method A

Step 1: Synthesis of Intermediate I-1.1

R1 (10.0 g, 28.55 mmol, purchased from Chem-Impex) is dissolved in DMFand 1 eq N-methylmorpholine is added. After addition of TBTU (9.26 g,28.55 mmol) the mixture is stirred for 30 min, before NH₄Cl (1.53 g,28.55 mmol) and further 3 eq N-methylmorpholine are added. After 1 h atr.t. the mixture is diluted with ethyl acetate, washed 2× with 1 N HCl,1× with water, 2× with aquous NaHCO₃ solution (10%), and 2× with water.The organic layer is dried over MgSO₄ and after filtration the solventin evaporated in vacuo. The product is crystallized with cold methanol.Yield 60% m/z 350/352 [M+H]+. rt 1.29 min, LC-MS Method V003_(—)003.

Step 2: Synthesis of Intermediate I-1.2

I-1.1 (10.7 g, 30.6 mmol) and 8.5 eq TFA in DCM are stirred for 1.5 h atr.t. The solvent is evaporated in vacuo, the residue is triturated with80 mL diethylether, and the residue is washed with diethylether. Yield94% m/z 249/251 [M+H]+, rt 0.92 min, LC-MS Method V003_(—)003

Step 3: Synthesis of Intermediate I-1.3

R2 (7.9 g, 31.8 mmol) mmol) (purchased from Aldrich or synthesized inanalogy to Tararov et al, Tetrahedron Asymmetry 13 (2002), 25-28) isdissolved in DCM, and 1 eq DIPEA and HATU (12 g, 31.6 mmol) are added.After stirring for 15 min at r.t. I-1.2 (10.5 g, 28.9 mmol) astrifluoroactetate and further 1.5 eq DIPEA are added, and the mixture isstirred for 2 h at r.t. The mixture is washed 3× with 1N HCl, 2× withaquous NaHCO₃ solution (10%) and 1× with water. The organic layer isdried over MgSO₄, filtered, and the filtrate is evaporated in vacuo. Theresidue is purified by MPLC.

Yield 78%, m/z=470/472 [M+H]+, rt 1.37 min, LC-MS Method V003_(—)003,TLC Rf=0.30 (silica gel Merck 60 F 254, DCM/MeOH 95:5).

Step 4: Synthesis of Intermediate I-1.4

I-1.3 (10.4 g, 22 mmol) and R3 (11.54 g, 48.4 mmol) are dissolved in DCMand stirred for 12 h at r.t. The mixture is washed 2× with 1N aceticacid, 2× with aquous NaHCO₃ solution (10%) and 2× with water. Theorganic layer is dried over MgSO₄, filtrated, and the filtrate isevaporated in vacuo. The residue is triurated with diethylether. Theprecipitate is purified by MPLC (DCM/MeOH 98:2). Yield 82%. m/z 454/456[M+H]+, rt 1.38 min, LC-MS Method V003_(—)003, TLC Rf=0.28 (silica gelMerck 60 F 254, DCM/MeOH 98:2).

Synthesis of Intermediate I-1.4.1

During the synthesis of Intermediate I-1.5.6 the bromothiophene I-1.4 isconverted to boronic ester I-1.4.1, which then is coupled with5-bromo-3H-isobenzofuran-1-one (5-bromophthalide).

For that purpose I-4.1 (1.5 g, 3.3 mmol) and bis-pinacolato-diboron(1.257 g, 4.952 mmol) are dissolved in 10 mL dioxane under argon.[1,1′-bis-(diphenylphosphino)-ferrocene]-palladium(II)-dichloride DCMcomplex (1:1) (269.6 mg, 0.33 mmol) and potassium acetate (972 mg, 9.9mmol) are added and the reaction vessel is again put under argon. Themixture is stirred for 6 h at 100° C. After cooling to r.t. water andethyl acetate are added and the organic layer is washed with water. Theorganic layer is dried, and the product is purified by MPLC(cyclohexane/ethyl acetate 6:4, 247 nm UV detection). The fractionscontaining the product are combined and the solvent is removed bylyophilization. Yield 16%. m/z 502 [M+H]+.

Step 5: Synthesis of Intermediate I-1.5

I-1.4 (250 mg, 0.55 mmol) and boronic acid R4 (99.8 mg, 0.005 mmol) aredissolved in 3 mL dioxan and 1 mL methanol in a microwave vial underargon. [1,1′-bis-(diphenylphosphino)-ferrocene]-palladium(II)-dichlorideDCM complex (1:1) (13.5 mg, 0.017 mmol) and 2M aqueous Na₂CO₃ solution(0.619 mL, 1.238 mmol) are added. The mixture is refluxed for 12 h, andafter cooling to r.t. the mixture is treated with water and ethylacetate, and the organic layer is washed 2× with water and dried overMgSO₄. After filtration the solution is evaporated in vacuo. Yield: 300mg crude product.

The following intermediates as shown in Table 2 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 2 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-1.5.1  I-1.4

521 0.74 X001_004 I-1.5.2  I-1.4

500 n.d. n.d. I-1.5.3  I-1.4

470 1.14 V012_S01 I-1.5.4  I-1.4

507 n.d. n.d. I-1.5.5 I-1.4

540 n.d. n.d. I-1.5.6    I-1.4.1

508 n.d. n.d. I-1.5.7  I-1.4

471 0.91 V012_S01 1-1.5.8  I-1.5.7 (by hydrogenation on at r.t. and 50psi with Pd/C in methanol)

473 n.d. n.d. I-1.5.9  I-1.4

614 n.d. n.d. I-1.5.10 I-1.4

536 n.d. n.d. I-1.5.11 I-1.4

536 n.d. n.d. I-1.5.12 I-1.4

530 1.18 X012_S01 I-1.5.13 1-1.4

530 0.62 X012_S01 I-1.5.14 I-1.4

535 1.20 V012_S01

Step 6: Synthesis of Example 1

I-1.5 (300 mg, 0.221 mmol) is dissolved in 8 mL acetonitrile, and sodiumiodide (247.4 mg, 1.65 mmol) and trimethylchlorosilane (209.5 μL, 1.65mmol) are added. After stirring for 1 h at r.t. 20 mL methanol areadded. The solvent is evaporated in vacuo and the residue is purified byreversed phase HPLC. The fractions which contain the product areevaporated, treated with acetonitrile and freeze-dried.

Yield 40%, m/z 395 [M+H]+, rt 0.55 min, LC-MS Method V001_(—)004.

Method B

Synthesis of Example 22

Step 1: Synthesis of Intermediate I-2.1

R5 (2.744 g, 12.46 mmol), R6 (4520 mg, 14.657 mmol),benzyltrimethylammonium chloride (272 mg, 1.466 mmol) and DCM (50 mL)are put together. Under stirring water (1.5 mL) and sodium hydroxidesolution (19 mol/L, 1.5 mL) are added. The reaction mixture is stirredfor 12 h at r.t and washed with water. The organic layer is dried overMgSO₄ and if necessary purified by reversed phase HPLC. Yield 94% crudeproduct.

The following intermediates as shown in Table 3 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 3 m/z LC-MS Intermediate Structure [M + H] + rt (min) methodI-2.1.2

429/431 1.48 V011_S01 I-2.1.3

445/447 0.89 X012_S01 I-2.1.5

413/415 1.46 V011_S01 I-2.1.6

395/397 1.49 V011_S01 I-2.1.7

n.d. n.d. n.d.

Step 2: Synthesis of Intermediate I-2.2

I-2.1 (6800 mg, 13.815 mmol) in dioxane (100 mL) aq. HCl (1 mol/L, 42mL) is added. The reaction mixture is stirred for 1.5 h. The solvent isevaporated in vacuo, crystallized in acetonitrile and washed withacetonitrile and diethylether. If necessary the product is purified byreversed phase HPLC. Yield 36.5% crude product.

The following intermediates as shown in Table 4 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 4 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-2.2.2 I-2.1.2

265/267 0.41 X012_S01 I-2.2.3 I-2.1.3

281/283 n.d. n.d. I-2.2.5 I-2.1.5

249/251 n.d. n.d. I-2.2.6 I-2.1.6

231/233 0.30 X012_S01 I-2.2.7 I-2.1.7

188 n.d. n.d.

Step 3: Synthesis of Intermediate I-2.3

To R2 (1380 mg, 5.554 mmol) in DMF (20 mL) diisopropylethylamine (0.87mL, 5.05 mmol) is added, and after cooling to 5° C., TBTU (1.7 g, 5.3mmol) and stirred for 15 min. Then intermediate I-2.2 as HCl salt (1840mg, 5.05 mmol) together with another 1.5 eq DIPEA is added and themixture stirred for 2 h at r.t. The mixture is treated with water andethyl acetate, and the organic layer is washed 2× with 1 N HCl, 1× withwater, 1× with aq. NaHCO₃ solution (5%) and 2× with water. The organiclayer is dried over MgSO₄ and after filtration the solvent is evaporatedin vacuo. Yield 92%, m/z 551/552/553/554 [M+H]+, rt 0.74 min, LC-MSMethod X012_S01, TLC Rf=0.28 silica gel Merck 60 F 254(cyclohexane/ethylacetate 7:3).

The following intermediates as shown in Table 5 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 5 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-2.3.2 I-2.2.2

488/490 0.74 X012_S01 I-2.3.3 I-2.2.3

504/506 1.33 V011_S01 I-2.3.5 I-2.2.5

474/476 1.24 V011_S01 I-2.3.6 I-2.2.6

454/456 1.26 V011_S01 I-2.3.7 I-2.2.7

411 n.d. n.d.

Step 4: Synthesis of Intermediate I-2.4

I-2.3 (1460 mg, 2.648 mmol) and R7 (759.55 mg, 2.78 mmol) are dissolvedin 15 mL acetonitrile divided in 13 microwave vials under argon.1,1-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (172.6 mg,0.265 mmol) and a 2M aq. solution of Na₂CO₃ (2.65 mL, 5.3 mmol) areadded and the reaction mixture again put under argon. After stirring for4 h at 80° C., the combined mixtures are diluted to a volume of 150 mLwith ethyl acetate and washed 3× with water. The organic layer is driedover MgSO₄ and filtrated. The filtrate is evaporated in vacuo, and theresidue is purified by MPLC (DCM/MeOH 98:2). Yield: 45%, m/z 618/620[M+H]+, rt 0.69 min, LC-MS Method X012_S01.

The following intermediates as shown in Table 6 are synthesized in asimilar fashion from the appropriate intermediate ((R,S)=1:1 mixture ofstereoisomers at the carbon adjacent to the nitrile group):

TABLE 6 m/z rt LC-MS Intermediate Educt Structure of Intermediate [M +H]+ (min) method I-2.4.2 I-2.3.2

529 1.34 V012_S01 I-2.4.3 I-2.3.2

555 0.68 X012_S01 I-2.4.4 I-2.3.2

486 0.78 X012_S01 I-2.4.5 1-2.3.3

502 1.40 V011_S01 1-2.4.7 1-2.3.5

539 0.69 Z001_002 1-2.4.8 1-2.3.6

521 1.17 V011_S01 1-2.4.9 1-2.3.7

522 n.d. n.d.

Step 5: Synthesis of Intermediate I-2.5

I-2.4 (330 mg, 0.534 mmol) is dissolved in 20 mL methanol andhydrogenated with 100 mg Pd/C for 24 h at 50 psi and r.t. Afterfiltering off the catalyst the solution is evaporated in vacuo. Yield:79%, m/z 539 [M+H]+, rt 1.20 min, LC-MS Method V012_S01.

Step 6: Synthesis of Example 22

To I-2.5 (225 mg, 0.418 mmol) in acetonitrile (15 mL) sodium iodide(187.8 mg, 1.253 mmol) and chlorotrimethylsilane (158.3 μL, 1.253 mmol)are added. The mixture is stirred for 1 h at r.t. 20 mL methanol areadded, stirred for 10 min and the solvent is evaporated in vacuo. Afterfiltering the filtrate is treated with 32.2 μL TFA and the product ispurified by semipreparative HPLC-MS. The fraction which contain theproduct are combined and freeze-dried. Yield 17%, m/z 439 [M+H]+, rt0.41 min, LC-MS Method X012_S01.

Method C

Synthesis of Example 5

Step 1: Synthesis of Intermediate I-3.1

R9 (9.343 g, 31.432) is dissolved in 20 mL THF and cooled down to −65°C. Tetramethylguanidine (3.952 g, 31.432 mmol) is added and stirred for15 min at this temperature. R8 (5 g, 28.575 mmol) dissolved in 10 mL THFis added, and the mixture is stirred for 12 h at r.t. After addition ofwater and ethyl acetate the organic layer is washed 3× with water anddried over MgSO₄. After filtering the filtrate is solvent is evaporatedin vacuo. The residue is crystallized with petrol ether, isolated byfiltration and washed with petrol ether. Yield 83%, m/z 346/348 [M+H]+,rt 0.63 min, LC-MS Method X012_S01, TLC Rf=0.33 (silica gel Merck 60 F254, DCM/methanol 98:2).

Step 2: Synthesis of Intermediate I-3.2

I-3.1 (1.5 g, 4.333 mmol) and R7 (1.243 g, 4.55 mmol) are dissolved in15 mL acetonitrile under argon. 1,1-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride (282.4 mg, 0.433 mmol) and 2M aq. Na₂CO₃ solution(4.333 mL, 8.666 mmol) are added and again put under argon. The mixtureis stirred 3 h at 85° C. After cooling to r.t. the mixture is filtered,and the filtrate is diluted with ethyl acetate to a volume of 200 mL.The organic layer is washed 2× with aq. NaHCO₃ solution (5%) and 2× withwater, dried over MgSO₄, filtrated, and the filtrate is evaporated invacuo. The residue is purified by MPLC (DCM/methanol 99:1, 240 nm UVdetection). The fractions containing the product are combined, and thesolvent is evaporated in vacuo. Yield 64% m/z 413 [M+H]+, rt 1.14 min,LC-MS Method V011_S01, TLC Rf=0.60 (silica gel Merck 60 F 254,DCM/methanol 99:1).

Step 3: Synthesis of Intermediate I-3.3

I-3.2 (1.11 g, 2.691 mmol) and(+)-1,2-bis-((2S,5S)-2,5-diethylphospholano)-benzene-(cyclooctadiene)-rhodium(I) trifluoromethanesulfonate (194.5 mg, 0.269 mmol) are suspended in 60mL methanol and hydrogenated for 18 h at r.t. and 50 psi. The catalystis removed by filtration, and the solvent is evaporated in vacuo. Theresidue is purified by MPLC (DCM/methanol 98:2 254 nm mass detection),the fractions containing the product are combined and the solvent isevaporated in vacuo.

Yield >98% m/z 415 [M+H]+, rt 1.16 min, LC-MS Method V011_S01, TLCRf=0.33 (silica gel Merck 60 F 254, DCM/methanol 98:2).

Step 4: Synthesis of Intermediate I-3.4

I-3.3 (1150 mg, 2.775 mmol) is dissolved in 40 mL methanol and LiOH(199.35 mg, 8.324 mmol) in 10 mL water are added. After stirring for 90min at r.t. the mixture is diluted with water to a volume of 150 mL,acidified with 2 N acetic acid to pH 4, extracted with ethyl acetate,and the organic layer is washed 3× with water. The combined organicphases are dried over MgSO₄, filtrated, and the solvent is evaporated invacuo. Yield 82% m/z 401 [M+H]+, rt 0.70 min, LC-MS Method V011_S01.

Step 5: Synthesis of Intermediate I-3.5

I-3.4 (910 mg, 2.273 mmol) and 1 eq DIPEA (0.391 mL) are dissolved in 20mL DMF, and TBTU (730 mg, 2.273 mmol) is added. After 20 min at r.t.NH₄Cl (607.8 mg, 11.363 mmol) and 5 eq DIPEA (1.955 mL) are added, andthe mixture is stirred for 3 h at r.t. Afterwards the mixture is dilutewith water to 100 mL, extracted 2× with ethyl acetate, and the combinedorganic layers are is washed 2× with aq. Na₂CO₃ solution (10%), 1× withwater, 2× with 1 N HCl and again 4× with water. The organic phase isdried over MgSO₄, filtrated, and the solvent is evaporated in vacuo. Theresidue is purified by MPLC (DCM/methanol 96:4, 254 nm UV detection).The fractions containing the product are combined and the solvent isevaporated in vacuo. Yield 51% m/z 400 [M+H]+, rt 0.98 min, LC-MS MethodV011_S01, TLC Rf=0.10 (silicagel Merck 60 F 254, DCM/methanol 95:5).

Step 6: Synthesis of Intermediate I-3.6

I-3.5 (450 mg, 1.127 mmol) and trifluoroacetic acid (6 mL) are dissolvedin 12 mL DCM and stirred for 90 min at r.t. Afterwards the solvent isevaporated in vacuo. Yield >98% m/z 300 [M+H]+, rt 0.69 min, LC-MSMethod V011_S01.

Step 7: Synthesis of Intermediate I-3.7

R2 (265.4 mg, 1.1 mmol) is dissolved in 5 mL DMF and treated with 1 eqDIPEA (143.6 mg). After addition of TBTU (388.5 mg, 1.21 mmol) themixture is stirred for 20 min at r.t. I-3.6 (465 mg, 1.125 mmol) and 1.5eq DIPEA (215.5 mg) are added and stirred for 12 h at r.t. The mixtureis diluted with ethyl acetate to a volume of 60 mL, washed 2× with 1 NHCl, 2× with water, 2× with aq. Na₂CO₃ solution (10%) and 3× with water,and the organic layer is dried over MgSO₄. After filtration the solventis evaporated in vacuo. Yield 82% m/z 523 [M+H]+, rt 1.05 min, LC-MSMethod V011_S01.

Step 8: Synthesis of Intermediate I-3.8

To I-3.7 (470 mg, 0.899 mmol) is added 10 mL DCM and Burgess reagent R3(535 mg, 2.248 mmol). The mixture is stirred for 12 h at r.t. and thesolvent is evaporated in vacuo. The residue is dissolved in ethylacetate, extracted 1× with 1 N HCl and 3× with water, and the organiclayer is dried over MgSO₄. After filtration the solvent is evaporated invacuo. Yield 99%.

Step 9: Synthesis of Example 5

I-3.8 (285 mg, 0.565 mmol) is dissolved in acetonitrile. Sodium iodide(254 mg, 1.694 mmol) and trimethylsilyl chloride (0.215 mL, 1.694 mmol)are added and the mixture is stirred for 1.5 h at r.t. After addition of10 mL methanol and stirring for additional 20 min at r.t. the solvent isevaporated in vacuo and the residue is dissolved in acetonitrile. Afterfiltration the product is purified by preparative HPLC (254 nm UVdetection). The fractions containing the product are combined andlyohilized Yield 40% m/z 405 [M+H]+, rt 0.81 min, LC-MS Method X018_S01.

Synthesis of Starting Materials/Educts Synthesis of1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine (R11)

R10 (800 mg, 3.1 mmol) is dissolved in DCM, N-methyl-piperazine (313 mg,3.1 mmol) is added and stirred for 12 h. After addition of 2 mL 1N HClunder stirring the phases are separated. The organic phase is dried overMgSO₄ and after filtration evaporated in vacuo. Yield: 84% m/z 319(M+H)+.

Step 1: Synthesis of Intermediate I-4.1

To R12 (25.0 g, 111 mmol) in acetonitrile (750 mL) is added MeI (15 mL,241 mmol) and K₂CO₃ (60.0 g, 434 mmol) and the reaction mixture isstirred at 60° C. for 2 h. The reaction mixture is filtered andconcentrated. Water and ethyl acetate are added to the residue. Theorganic layer is extracted twice with water, dried over MgSO₄ andconcentrated. Yield 56%, m/z 240/242 [M+H]+, rt 0.48 min, LC-MS MethodX001_(—)004.

Step 2: Synthesis of Intermediate I-4.2

I-4.1 (15.0 g, 63 mmol) and hydrazine hydrate (30 mL, 618 mmol) areheated to 125° C. for 72 h. To the cool reaction mixture DCM is addedand extracted with water and 1 M HCl. The organic layer is dried overMgSO₄ and concentrated. The crystallized residue is dissolved in DCM,methanol is added and the DCM is removed in vacuo. The crystallizedproduct is filtered by sunction and washed with cold methanol. Yield63%, m/z 226/228 [M+H]+, rt 1.16 min, LC-MS Method V001_(—)003.

Step 3: Synthesis of Intermediate R7

To I-4.2 (32.0 g, 142 mmol) in anhydrous dioxane (400 mL) is added R3(54.4 g, 241 mmol) and potassium acetate (41.6 g, 424 mmol). The mixtureis purged with Argon,[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a complexwith dichloromethane (11.2 g, 14 mmol) is added and the mixture isheated to 90° C. for 2 h. The reaction mixture is diluted with ethylacetate and water, the organic layer is washed with water, dried overMgSO₄ and concentrated. The residue is purified via flash chromatography(cyclohexane/EA=70:30). Yield 72%, m/z 274 [M+H]+, rt 0.67 min, LC-MSMethod VO11_S01.

The following intermediates as shown in Table 7 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 7 Intermediate Structure of Intermediate m/z [M + H]+ rt (min)LC-MS method R7.1

325 [M + NH₄]+ 0.30 X018_S01 R7.2

285 n.d. n.d. R7.3

289 n.d. n.d. R7.4

289 n.d. n.d. R7.5

288 0.62 V011_S01 R7.6

260 0.97 V012_S01 R7.7

274 1.04 V012_S01

All other boronic acid derivatives R4 and R7 are purchased or preparedby literature known procedures.

Synthesis of 5-chloromethyl-2,3-dibromo-4-fluoro-thiophene (R6)

Step 1: Synthesis of Intermediate I-5.1

R13 (6400 mg, 20.128 mmol), purchased from Goldenbridge, and lithiumhydroxide (2410.3 mg, 100.642 mmol) are suspended in 130 mL THF andstirred 3 h at room temperature. The mixture is diluted with water to500 mL, acidified with 1 N HCl, extracted with diethyl ether, and theorganic layer is washed 3× with water and dried over MgSO₄. Afterfiltration the solvent is evaporated in vacuo. Yield: 97%.

Step 2: Synthesis of Intermediate I-5.2

I-5.1 (5950 mg mg, 19.577 mmol) is dissolved in 200 mL THF and1,1′-Carbonyldiimidazole (3491.8 mg, 21.534 mmol) is added. After 1 h at50° C. and 30 min at room temperature NaBH₄ (2221.758 mg, 58.73 mmol) isadded and afterwards dropwise 50 mL water. After stirring for 2 h atroom temperature the mixture is diluted with water to 800 mL andacidified with acetic acid. The solution is extracted 2× with diethylether, the combined organic layers are washed 2× with 1 N acetic acid,3× with water, 2× with aq. Na₂CO₃ solution (10%) and 2× with water. Theorganic phase is dried over MgSO₄, filtrated, and the solvent isevaporated in vacuo. Yield: 92%.

The following intermediates as shown in Table 8 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 8 Intermediate Structure m/z [M + H] + rt (min) LC-MS method1-5.2.1 (directly from the ester without CDI with MeOH)

n.d. Rf = 0.50 Merck silica gel 60F 254 Cyclohexane/ethyl acetate 8:21-5.2.2 (directly from the ester without CDI with MeOH)

265 (M + Na)+ n.d. n.d. 1-5.2.3 (directly from the ester with LiAlH₄without water)

210 (M*+) Rf = 0.33 Merck silica gel 60F 254 Cyclohexane/ethyl acetate7:3 1-5.2.4 (directly from the aldehyde without water in ethanol)

175/177 0.40 X012_S01

Step 3: Synthesis or R6

I-5.2 (5200 mg, 17.934 mmol) and triethylamine (3.022 mL, 21.521 mmol)are dissolved in 50 mL DCM and treated with methanesulfonylchloride(1.458 mL, 18.831 mmol) below 5° C. After stirring for 12 h at roomtemperature the solvent is evaporated in vacuo and the residue isdissolved in diethyl ether and washed 2× with 1 N HCl and 3× with water.After drying over MgSO₄ and filtrating the solvent is evaporated invacuo. Yield: 82%.

The following intermediates as shown in Table 9 are synthesized in asimilar fashion from the appropriate intermediates:

TABLE 9 Intermediate Structure m/z [M + H]+ rt (min) LC-MS method R6.1(thionyl chloride is used instead)

n.d. Rf = 0.65 Merck silica gel 60F 254 Cyclohexane/ethyl acetate 8:2R6.2 (thionyl chloride is used instead)

260 (M*+) n.d. n.d. R6.3

n.d. Rf = 0.42 Merck silica gel 60F 254 Cyclohexane/ethyl acetate 7:3R6.4

210 (M*+) n.d. n.d.

Synthesis of(1S,2S,4R)-3-[(tert.-butoxy)carbonyl]-3-azabicyclo[2.2.1]heptane-2-carboxylate(R2)

The compound is commercially available or can be synthesized in analogyto Tararov et al, Tetrahedron Asymmetry 13 (2002), 25-28.

Step 1: Synthesis of Intermediate I-6.1

A solution of R17 (44.9 g, 0.44 mol), freshly distilled from acommercially available solution in toluene (at 50 mbar, 55° C.) indiethylether (300 ml) is cooled at −10° C., followed by dropwiseaddition of R14 (53 g, 440 mmol), keeping the temperature below 0° C.After complete addition, MgSO4*H20 (91 g, 660 mmol) is added, and theresulting mixture stirred at room temperature overnight. The mixture isfiltrated, the solution phase concentrated in vacuo and the residuedestilled under reduced pressure to yield I-6.1 (47 g, m/z 206 [M+H]+,rt 1.29 min, LC-MS Method V003_(—)003). The product is used withoutfurther purification.

Step 2: Synthesis of Intermediate I-6.2

A solution of I-6.1 (47 g; 229 mmol) and R15 (30 g; 458 mmol) (freshlydistilled from dicyclopentadien) in DMF (150 ml) and 120 μl water iscooled to 0° C., before TFA (18 ml; 234 mmol) is added dropwise. Themixture is stirred overnight at room temperature, then added to asolution of 40 g NaHCO₃ in 1200 ml water and extracted withdiethylether. The organic layer is separated, washed subsequently withaqueous NaHCO₃ and water, dried over MgSO4, and concentrated in vacuo.The residue is worked up by column chromatography on silica(cyclohexane/ethyl acetate=9:1) to yield I-6.2 (Yield 52% m/z 272[M+H]+, rt 0.42 min, LC-MS Method X001_(—)004)

Step 3: Synthesis of Intermediate I-6.3

To a solution of I-6.2 (24.8 g, 91 mmol) in ethanol (250 ml),Raney-nickel is added (2.5 g) and reacted at 50 psi under a hydrogenatmosphere at room temperature. The catalyst is filtered of, the issolution concentrated in vacuo and the residue worked up bychromatography on silica (cyclohexane/ethyl acetate 9:1). Afterevaporation of the organic solvent, the obtained product is redissolvedin diethylether and triturated with solution of HCl in dioxane,concentrated in vacuo, redissolved in 200 ml ethanol and concentrated invacuo to yield I-6.3: (Yield 78% m/z 274 [M+H]+, rt 0.42 min, LC-MSMethod X001_(—)004).

Step 4: Synthesis of Intermediate I-6.4

To a solution of I-6.3 (22 g, 71 mmol) in ethanol (250 ml), 10% Pd/C isadded (2.5 g) and reacted at 15 bar under a hydrogen atmosphere at roomtemperature. The catalyst is filtered of, the solution concentrated invacuo. The residue is washed with diisopropylether to yield I-6.4.(Yield 98% m/z 170 [M+H]+, rt 0.48 min, LC-MS Method V001_(—)007).

Step 5: Synthesis of Intermediate I-6.5

To I-6.4 in a solution of triethylamin (24.6 ml), THF (150 ml) and water(2 ml), R16 (15.9 g; 73 mmol) is added and the resulting mixture stirredfor 40 hours at room temperature, then concentrated in vacuo. Ethylacetate is added to the residue, subsequently extracted with water, 1 Nacidic acid and water, before the organic layer is dried over MgSO4 andconcentrated in vacuo to yield I-6.5. (Yield 95% m/z 270 [M+H]+, rt 1.33min, LC-MS Method V003_(—)003).

Step 6: Synthesis of R2

A mixture of I-6.5 (16.9 g; 63 mmol) in acetone (152 ml), water (50 ml)and lithium hydroxide (3 g, 126 mmol) is stirred overnight at roomtemperature. Water (100 ml) was added, the volume reduced in vacuobefore cooling to 0° C. followed by the addition of 1N aqueous HCl toacidify to a pH of 2-3, immediately followed by extraction with ethylacetate. The organic layer was washed with water, dried (MgSO4) andconcentrated. To the residue, dichloromethane (100 ml) and cyclohexane(100 ml) was added, the volume reduced in vacuo by half and the mixturetemperated at 15° C. The precipitate was filtered of, washed withcyclohexane to yield R2 (Yield 66%, m/z 242 [M+H]+).

EXAMPLES

(rt=retention time) Stereochemistry at the carbon atom adjacent to thenitrile group is assigned: Stereo bond means S-isomer, non-stereo bondmeans 1:1 mixture of stereoisomers.

TABLE 10 Syn. Yield Example Structure Educt Method [%] 1

I-1.5 A 40 2

I-1.5.13 A 26 3

I-1.5.1 A 47 4

I-1.5.14 A 40 5

1-3.8 C 40 6

I-2.3.2 B 63 7

I-2.4.2 B 86 8

I-2.4.3 B 29 9

I-2.4.4 B 25 10

I-2.3.3 B 59 11

I-2.4.5 B 49 12

I-2.4.9 B 38 13

I-2.4.7 B 12 14

I-1.5.2 A 34 15

I-2.4.8 B 37 16

I-1.5.3 A 40 17

I-1.5.4 A 59 18

I-1.5.5 A 25 19

I-1.5.6 A 51 20

I-1.5.8 A 31 21

I-2.4 B 67 22

I-2.5 B 17 23

I-1.5.9 A 76 24

I-1.5.10 A 57 25

I-1.5.11 A 90 26

I-1.5.12 A 66

Analytical Data of Examples

# m/z [M + H]+ rt [min] LC-MS-Method 1 395 0.55 X001_004 2 430 0.38X012_S01 3 421 0.51 X001_004 4 435 0.85 V012_S01 5 405 0.81 X018_S01 6388/390 0.48 X012_A15 7 429 0.52 X012_A15 8 455 0.46 X012_A15 9 386 0.55X012_S01 10 404/406 0.51 X012_S01 11 402 1.29 V011_S01 12 422 0.76V012_S01 13 439 0.82 V018_S01 14 400 0.84 V012_S01 15 421 0.39 X012_S0116 370 0.78 V012_S01 17 407 0.78 V012_S01 18 440 0.81 V012_S01 19 4070.84 V012_S01 20 373 0.61 V012_S01 21 518/520 0.45 X012_S01 22 439 0.41X012_S01 23 514 0.79 V012_S01 24 436 0.95 V012_S01 25 436 0.93 V012_S0126 430 0.39 X012_S01

Abbreviations

ACN acetonitrile aq. aqueous BOC tert. butyloxycyrbonyle- d day DCMdichloromethane DIPEA n,n-diisopropylethylamine DIPE diisopropyl etherDMAP 4-dimethylaminopyridine DMF n,n-dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate FA formic acid h hour HATUo-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluoro-phosphate LiOH lithium hydroxide MeOH methanol Rf Ratio offronts RT, r.t. room temperature e.g. 15-25° C. rt retention time sat.saturated SI trimethylsilyl iodide TBME tert-butyl methyl ether TBTUo-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N′,N′- tetramethyluroniumtetrafluoroborate TEA triethylamine TFA trifluoroacetic acid THFtetrahydrofuran TSA toluene sulfonic acid

Pharmacological Data

Other features and advantages of the present invention will becomeapparent from the following more detailed examples which illustrate, byway of example, the principles of the invention.

Inhibition of Human DPPI (Cathepsin C)

Materials: Microtiterplates (Optiplate-384 F) were purchased fromPerkinElmer (Prod. No. 6007270). The substrate Gly-Arg-AMC was fromBiotrend (Prod.-No. 808756 Custom peptide). Bovine serum albumin (BSA;Prod. No. A3059) and Dithiothreitol (DTT; Prod. No D0632) were fromSigma. TagZyme buffer was from Riedel-de-Haen (Prod.-No. 04269), NaClwas from Merck (Prod.-No. 1.06404.1000) and morpholinoethane sulfonicacid (MES), was from Serva (Prod.-No. 29834). The DPP1 inhibitorGly-Phe-DMK was purchased from MP Biomedicals (Prod.-No. 03DK00625). Therecombinant human DPPI was purchased from Prozymex. All other materialswere of highest grade commercially available.

The following buffers were used: MES buffer: 25 mM MES, 50 mM NaCl, 5 mMDTT, adjusted to pH 6.0, containing 0.1% BSA; TAGZyme Buffer: 20 mMNaH₂PO₄, 150 mM NaCl adjusted to pH 6.0 with HCl

Assay conditions: The recombinant human DPPI was diluted in TAGZymebuffer to 1 U/ml (38.1 μg/ml, respectively), and then activated bymixing in a 1:2 ratio with a Cysteamine aqueous solution (2 mM) andincubating for 5 min at room temperature.

Five uL test compound (final concentration 0.1 nM to 100 μM) in aquabidest (containing 4% DMSO, final DMSO concentration 1%) were mixed with10 μL of DPPI in MES buffer (final concentration 0.0125 ng/μL) andincubated for 10 min. Then, 5 μL of substrate in MES buffer (finalconcentration 50 μM) were added. The microtiter plates were thenincubated at room temperature for 30 min. Then, the reaction was stoppedby adding 10 μL of Gly-Phe-DMK in MES-buffer (final concentration 1 μM).The fluorescence in the wells was determined using a Molecular DevicesSpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an EnvisionFluorescence Reader (Ex 355 nm, Em 460 nm).

Each assay microtiter plate contained wells with vehicle controls (1%DMSO in bidest+0.075% BSA) as reference for non-inhibited enzymeactivity (100% Ctl; high values) and wells with inhibitor (Gly-Phe-DMK,in bidest+1% DMSO+0.075% BSA, final concentration 1 μM) as controls forbackground fluorescence (0% Ctl; low values).

The analysis of the data was performed by calculating the percentage offluorescence in the presence of test compound in comparison to thefluorescence of the vehicle control after subtracting the backgroundfluorescence using the following formula:(RFU(sample)−RFU(background))*100/(RFU(control)−RFU(background))

Data from these calculations were used to generate IC₅₀ values forinhibition of DPPI, respectively.

Inhibition of DPPI # Ki [μM] 1 0.0137 2 0.0173 3 0.0032 4 0.0021 50.1765 6 0.0641 7 0.0393 8 0.1036 9 0.062 10 0.0358 11 0.0728 12 0.014913 0.0617 14 0.0134 15 0.0419 16 0.0171 17 0.0042 18 0.027 19 0.0009 200.0379 21 0.0036 22 0.0022 23 0.0029 24 0.0219 25 0.004 26 0.0167

Inhibition of Human Cathepsin K

Materials: Microtiterplates (Optiplate-384 F were purchased fromPerkinElmer (Prod. No. 6007270). The substrate Z-Gly-Pro-Arg-AMC wasfrom Biomol (Prod.-No. P-142). L-Cysteine (Prod. No. 168149) was fromSigma. Sodium actetate was from Merck (Prod.-No. 6268.0250), EDTA wasfrom Fluka (Prod.-No. 03680). The inhibitor E-64 was purchased fromSigma (Prod.-No. E3132). The recombinant human Cathepsin K proenzyme waspurchased from Biomol (Prod. No. SE-367). All other materials were ofhighest grade commercially available.

The following buffers were used: Activation buffer: 32.5 mM sodiumacetate, adjusted to pH 3.5 with HCl; Assay buffer: 150 mM sodiumacetate, 4 mM EDTA, 20 mM L-Cysteine, adjusted to pH 5.5 with HCl,

Assay conditions: To activate the proenzyme, 5 μl procathepsin K weremixed with 1 ul activation buffer, and incubated at room temperature for30 min.

5 μL test compound (final concentration 0.1 nM to 100 μM) in aqua bidest(containing 4% DMSO, final DMSO concentration 1%) were mixed with 10 uLof Cathepsin K in assay buffer (final concentration 2 ng/μL) andincubated for 10 min. Then 5 μL of substrate in assay buffer (finalconcentration 12.5 μM) were added. The plates were then incubated atroom temperature for 60 min. Then, the reaction was stopped by adding 10μL of E64 in assay buffer (final concentration 1 μM). The fluorescencein the wells was determined using a Molecular Devices SpectraMax M5Fluorescence Reader (Ex 360 nm, Em 460 nm).

Each assay microtiter plate contains wells with vehicle controls (1%DMSO in bidest) as reference for non-inhibited enzyme activity (100%Ctl; high values) and wells with inhibitor (E64 in bidest+1% DMSO, finalconcentration 1 μM) as controls for background fluorescence (0% Ctl; lowvalues). The analysis of the data was performed by calculating thepercentage of fluorescence in the presence of test compound incomparison to the fluorescence of the vehicle control after subtractingthe background fluorescence:(RFU(sample)−RFU(background))*100/(RFU(control)−RFU(background))

Data from these calculations were used to generate IC₅₀ values forinhibition of Cathepsin K, respectively.

Combinations

The compounds of general formula I may be used on their own or combinedwith other active substances of formula I according to the invention.The compounds of general formula I may optionally also be combined withother pharmacologically active substances. These include,β2-adrenoceptor-agonists (short and long-acting), anti-cholinergics(short and long-acting), anti-inflammatory steroids (oral and topicalcorticosteroids), cromoglycate, methylxanthine,dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4-inhibitors,PDE7-inhibitors, LTD4 antagonists, EGFR-inhibitors, Dopamine agonists,PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor(BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, HistamineH4 receptor antagonists, dual Histamine H1/H3-receptor antagonists,PI3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases asfor example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAPkinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP,inhibitors of the NF-κB signalling pathway as for example IKK2 kinaseinhibitors, iNOS inhibitors, MRP4 inhibitors, leukotriene biosyntheseinhibitors as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors,Non-steroidal anti-inflammatory agents (NSAIDs), CRTH2 antagonists,DP1-receptor modulators, Thromboxane receptor antagonists, CCR3antagonists, CCR4 antagonists, CCR1 antagonists, CCR5 antagonists, CCR6antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30antagonists, CXCR³ antagonists, CXCR⁴ antagonists, CXCR² antagonists,CXCR¹ antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR³antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1-Phosphatereceptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosinereceptor modulators as for example A2a-agonists, modulators ofpurinergic rezeptors as for example P2X7 inhibitors, Histone Deacetylase(HDAC) activators, Bradykinin (BK1, BK2) antagonists, TACE inhibitors,PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1-betaconverting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators,HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIPagonists, GABAa receptor antagonist, ENaC-inhibitors,Prostasin-inhibitors, Matriptase-inhibitors, Melanocortin receptor(MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelinantagonists, TNFα antagonists, anti-TNF antibodies, anti-GM-CSFantibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40antibodies, mucoregulators, immunotherapeutic agents, compounds againstswelling of the airways, compounds against cough, VEGF inhibitors,NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinationsof two or three active substances.

Preferred are betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors,5-LO-inhibitors, Histamine receptor antagonists and SYK-inhibitors,NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinationsof two or three active substances, i.e.:

-   -   Betamimetics with corticosteroids, PDE4-inhibitors,        CRTH2-inhibitors or LTD4-antagonists,    -   Anticholinergics with betamimetics, corticosteroids,        PDE4-inhibitors, CRTH2-inhibitors or LTD4-antagonists,    -   Corticosteroids with PDE4-inhibitors, CRTH2-inhibitors or        LTD4-antagonists    -   PDE4-inhibitors with CRTH2-inhibitors or LTD4-antagonists    -   CRTH2-inhibitors with LTD4-antagonists.

Indications

The compounds of the invention and their pharmaceutically acceptablesalts have activity as pharmaceuticals, in particular as inhibitors ofdipeptidyl peptidase I activity, and thus may be used in the treatmentof:

1. respiratory tract: obstructive diseases of the airways including:asthma, including bronchial, allergic, intrinsic, extrinsic,exercise-induced, drug-induced (including aspirin and NSAID-induced) anddust-induced asthma, both intermittent and persistent and of allseventies, and other causes of airway hyper-responsiveness; chronicobstructive pulmonary disease (COPD); bronchitis, including infectiousand eosinophilic bronchitis; emphysema; alpha1-antitrypsin deficiency,bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and relateddiseases; hypersensitivity pneumonitis; lung fibrosis, includingcryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias,fibrosis complicating anti-neoplastic therapy and chronic infection,including tuberculosis and aspergillosis and other fungal infections;complications of lung transplantation; vasculitic and thromboticdisorders of the lung vasculature, polyangiitis (Wegener Granulomatosis)and pulmonary hypertension; antitussive activity including treatment ofchronic cough associated with inflammatory and secretory conditions ofthe airways, and iatrogenic cough; acute and chronic rhinitis includingrhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonalallergic rhinitis including rhinitis nervosa (hay fever); nasalpolyposis; acute viral infection including the common cold, andinfection due to respiratory syncytial virus, influenza, coronavirus(including SARS) and adenovirus;

2. skin: psoriasis, atopic dermatitis, contact dermatitis or othereczematous dermatoses, and delayed-type hypersensitivity reactions;phyto- and photodermatitis; seborrhoeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosus et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia greata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme; cellulitis, both infective and non-infective;panniculitis;cutaneous lymphomas, non-melanoma skin cancer and otherdysplastic lesions; drug-induced disorders including fixed drugeruptions;

3. eyes: blepharitis; conjunctivitis, including perennial and vernalallergic conjunctivitis; iritis; anterior and posterior uveitis;choroiditis; autoimmune, degenerative or inflammatory disordersaffecting the retina; ophthalmitis including sympathetic ophthalmitis;sarcoidosis; infections including viral, fungal, and bacterial;

4. genitourinary: nephritis including interstitial andglomerulonephritis; nephrotic syndrome; cystitis including acute andchronic (interstitial) cystitis and Hunner's ulcer; acute and chronicurethritis, prostatitis, epididymitis, oophoritis and salpingitis;vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male andfemale);

5. allograft rejection: acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin orcornea or following blood transfusion; or chronic graft versus hostdisease;

6. other auto-immune and allergic disorders including rheumatoidarthritis, irritable bowel syndrome, systemic lupus erythematosus,multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison'sdisease, diabetes mellitus, idiopathic thrombocytopaenic purpura,eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndromeand Sazary syndrome;

7. oncology: treatment of common cancers including prostate, breast,lung, ovarian, pancreatic, bowel and colon, stomach, skin and braintumors and malignancies affecting the bone marrow (including theleukaemias) and lymphoproliferative systems, such as Hodgkin's andnon-Hodgkin's lymphoma; including the prevention and treatment ofmetastatic disease and tumour recurrences, and paraneoplastic syndromes;and,

8. infectious diseases: virus diseases such as genital warts, commonwarts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus,molluscum contagiosum, variola, human immunodeficiency virus (HIV),human papilloma virus (HPV), cytomegalovirus (CMV), varicella zostervirus (VZV), rhinovirus, adenovirus, coronavirus, influenza,para-influenza; bacterial diseases such as tuberculosis andmycobacterium avium, leprosy; other infectious diseases, such as fungaldiseases, chlamydia, Candida, aspergillus, cryptococcal meningitis,Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection and leishmaniasis.

9. pain: Recent literature data from Cathepsin C-deficient mice point toa modulatory role of Cathepsin C in pain sensation. Accordingly,inhibitors of Cathepsin C may also be useful in the clinical setting ofvarious form of chronic pain, e.g. inflammatory or neuropathic pain.

For treatment of the above-described diseases and conditions, atherapeutically effective dose will generally be in the range from about0.01 mg to about 100 mg/kg of body weight per dosage of a compound ofthe invention; preferably, from about 0.1 mg to about 20 mg/kg of bodyweight per dosage. For Example, for administration to a 70 kg person,the dosage range would be from about 0.7 mg to about 7000 mg per dosageof a compound of the invention, preferably from about 7.0 mg to about1400 mg per dosage. Some degree of routine dose optimization may berequired to determine an optimal dosing level and pattern. The activeingredient may be administered from 1 to 6 times a day.

The actual pharmaceutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the active ingredient will be administered atdosages and in a manner which allows a pharmaceutically effective amountto be delivered based upon patient's unique condition.

What we claim:
 1. A compound of formula 1

wherein X is selected from among S and O; Y is selected from among N andCH; R¹ is independently selected from among H, C₁₋₆-alkyl-, halogen,HO—, C₁₋₆-alkyl-O—, H₂N—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂N— andC₁₋₆-alkyl-C(O)HN—; or two R¹ are together C₁₋₄-alkylene; R² is selectedfrom among R^(2.1); aryl-; optionally substituted with one, two or threeresidues independently selected from R^(2.1); optionally substitutedwith one R^(2.3); C₅₋₁₀-heteroaryl-; containing one, two, three or fourheteroatoms independently selected from among S, S(O), S(O)₂, O and N,wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein nitrogenatoms of the ring are optionally and independently from each othersubstituted with one, two or three R^(2.2); wherein a carbon atom of thering is optionally substituted with one R^(2.3); a nitrogen atom of thering is optionally substituted with one R^(2.4); C₅₋₁₀-heterocyclyl-;containing one, two, three or four heteroatoms independently selectedfrom among S, S(O), S(O)₂, O and N, wherein the ring is fully orpartially saturated, wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two or three or fourR^(2.1); wherein nitrogen atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.2); wherein a carbon atom of the ring is optionally substitutedwith one R^(2.3) or one R^(2.5); a nitrogen atom of the ring isoptionally substituted with one R^(2.4) or R² and R⁴ are together withtwo adjacent carbon atoms of the heteroaryl ring a 5- or 6-membered arylor heteroaryl, containing one, two or three heteroatoms independentlyselected from among S, S(O), S(O)₂, O and N, wherein carbon atoms of thering are optionally and independently from each other substituted withone, two or three R^(2.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.2); R^(2.1) is independently selected from among H,halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₆-alkylene-, R^(2.1.1)-A-,C₁₋₆-alkyl-A-, C₃₋₈-cycloalkyl-A-, C₁₋₆-haloalkyl-A-,R^(2.1.1)—C₁₋₆-alkyl-A-, C₁₋₆-alkyl-A-C₁₋₆-alkylene-,C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-, C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-,R^(2.1.1)—C₁₋₆-alkylene-A-C₁₋₆-alkylene-, R^(2.1.1)-A-C₁₋₆-alkylene-,HO—C₁₋₆-alkylene-A-, HO—C₁₋₆-alkylene-A-C₁₋₆-alkylene-, C₁₋₆-alkylO—C₁₋₆-alkylene-A- and C₁₋₆-alkyl-O—C₁₋₆-alkylene-A-C₁₋₆-alkylene-R^(2.1.1) is independently selected from among aryl-; optionallysubstituted independently from each other with one, two or threeR^(2.1.1.1); C₅₋₁₀-heteroaryl-; containing one, two, three or fourheteroatoms independently selected from among S, S(O), S(O)₂, O and N,wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1.1.1); whereinnitrogen atoms of the ring are optionally and independently from eachother substituted with one, two or three R^(2.1.1.2);C₅₋₁₀-heterocyclyl-; containing one, two, three or four heteroatomsindependently selected from among S, S(O), S(O)₂, O and N, wherein thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three or four R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); R^(2.1.1.1) is independently selected from amonghalogen, HO—, O═, C₁₋₆-alkyl-, C₁₋₆-alkyl-O—, C₁₋₆-haloalkyl- andC₁₋₆-haloalkyl-O— and C₃₋₈-cycloalkyl-; R^(2.1.1.2) is independentlyselected from among O═, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,C₁₋₆-alkyl-O—C₁₋₆-alkyl-, H(O)C—, C₁₋₆-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-; R^(2.2) isindependently selected from among H-A-C₁₋₆-alkylene-, C₃₋₈-cycloalkyl-,C₁₋₆-alkyl-A-C₁₋₆-alkylene-, C₃₋₈-cycloalkyl-A-C₁₋₆-alkylene-,C₁₋₆-haloalkyl-A-C₁₋₆-alkylene-, C₁₋₆-alkyl-S(O)₂—, C₁₋₆-alkyl-C(O)— andR^(2.1.1)-A-; R^(2.3) and R⁴ are together selected from among —O—, —S—,—N(R^(2.3.1))—, —C(O)N(R^(2.3.1))—, —N(R^(2.3.1))C(O)—,—S(O)₂N(R^(2.3.1))—, —N(R^(2.3.1))S(O)₂—, —C(O)O—, —OC(O)—, —C(O)—,—S(O)—, —S(O)₂—, R^(2.3), R^(2.3), —C(R^(2.3.2))═C(R^(2.3.2))—, —C═N—,—N═C—, —C(R^(2.3.2))₂—O—, —O—C(R^(2.3.2))₂—,—C(R^(2.3.2))₂N(R^(2.3.1))—, —N(R^(2.3.1))C(R^(2.3.2))₂— and—C₁₋₄-alkylene-; R^(2.3.1) is independently selected from among H,C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and, (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-;R^(2.3.2) is independently selected from among H, C₁₋₆-alkyl-,C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.4)and R⁴ are together selected from among —N(R^(2.4.1))—,—C(O)N(R^(2.4.1))—, —N(R^(2.4.1))C(O)—, —S(O)₂N(R^(2.4.1))—,—N(R^(2.4.1))S(O)₂—, —C(O)—, —S(O)—, —S(O)₂—,—C(R^(2.4.2))═C(R^(2.4.2))—, —C═N—, —C(R^(2.4.2))₂N(R^(2.4.1))—,—N(R^(2.4.1))C(R^(2.4.2))₂— and —C₁₋₄-alkylene-; and R^(2.4.1) isindependently selected from among H, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-;C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-,H₂N—C₁₋₄-alkylene-, (C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and(C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.4.2) is independently selected fromamong H, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-,HO—C₁₋₄-alkylene-, (C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R^(2.5)and R⁴ are together selected from among —C(R^(2.5.1))═, ═C(R^(2.5.1))—and —N═; and R^(2.5.1) is independently selected from among H,C₁₋₆-alkyl-, C₁₋₆-haloalkyl-; C₃₋₈-cycloalkyl-, HO—C₁₋₄-alkylene-,(C₁₋₄-alkyl)-O—C₁₋₄-alkylene-, H₂N—C₁₋₄-alkylene-,(C₁₋₄-alkyl)HN—C₁₋₄-alkylene- and (C₁₋₄-alkyl)₂N—C₁₋₄-alkylene-; R³ is Hor F; R⁴ is independently selected from among H, F, Cl, Br,phenyl-H₂C—O—, HO—, C₁₋₆-alkyl-, C₁₋₆-haloalkyl-, C₃₋₈-cycloalkyl-,C₁₋₆-alkyl-O—, C₁₋₆-haloalkyl-O—, C₁₋₆-alkyl-HN—, (C₁₋₆-alkyl)₂-HN—,C₁₋₆-alkyl-HN—C₁₋₄-alkylene- and (C₁₋₆-alkyl)₂-HN—C₁₋₄-alkylene-; A is abond or independently selected from among —O—, —S—, —N(R⁵)—,—C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—,—S(O)(═NR⁵)—N(R⁵)—, —N(R⁵)(NR⁵═)S(O)—, —S(═NR⁵)₂—N(R⁵)—,—N(R⁵)(NR⁵═)₂S—, —C(R⁵)═C(R⁵)—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—,—S(O)₂—, —S(═NR⁵)—, —S(O)(═NR⁵)—, —S(═NR⁵)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S—and —N═(O)(R⁵)S—; R⁵ is independently selected from among H, C₁₋₆-alkyl-and NC—; or a salt thereof.
 2. The compound of formula 1, according toclaim 1, wherein R¹ is R^(1.a) and R^(1.a) is independently selectedfrom among H, C₁₋₄-alkyl-, F and HO—.
 3. The compound of formula 1,according to claim 1, wherein R⁴ is R^(4.a) and R^(4.a) is H, F, Cl, Br,phenyl-H₂C—O—, HO—, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-,C₃₋₆-cycloalkyl-C₁₋₄-alkyl-O— and C₁₋₄-haloalkyl-O—.
 4. The compound offormula 1, according to claim 1, wherein R⁴ is R^(4.b) and R^(4.b) is Hor F.
 5. The compound of formula 1, according to claim 1, wherein A isA^(a) and A^(a) is a bond or independently selected from among —O—,—C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)—, —N(R⁵)S(O)₂—, —C(O)O—, —OC(O)—,—C(O)—, —S(O)₂—, —(R⁵)(O)S═N—, —(R⁵N═)(O)S— and —N═(O)(R⁵)S— and R⁵ isR^(5.a) and R^(5.a) is independently selected from among H, C₁₋₄-alkyl-and NC—.
 6. The compound of formula 1, according to claim 1, wherein R²is R^(2.1) and R^(2.1) is R^(2.1.a) and R^(2.1.a) is selected from amongH, halogen, NC—, O═, HO—, H-A-, H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-,C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-, C₁₋₄-haloalkyl-A-,R^(2.1.1)—C₁₋₄-alkylene-A-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from among aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O or N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
 7. The compound offormula 1, according to claim 1, wherein R² is R^(2.d) and R^(2.d) isphenyl; optionally substituted with one, two or three residuesindependently selected from R^(2.1) and R^(2.1) is R^(2.1.a) andR^(2.1.a) is selected from among H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from among aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.12); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl.
 8. The compound offormula 1, according to claim 1, wherein R² is R^(2.q) and R^(2.q) isselected from among formulas (b1), (c1), (d1), (e1), (f1) and (g1),

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1); wherein nitrogenatoms of the ring are optionally and independently from each othersubstituted with one, two or three R^(2.2), R^(2.1) is R^(2.1.a) andR^(2.1.a) is selected from among H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from among aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected from amongH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-.
 9. The compound of formula 1, according to claim 1,wherein R² is R^(2.j) and R^(2.j) is selected from among

and

wherein carbon atoms of the ring are optionally and independently fromeach other substituted with one, two or three R^(2.1), wherein possiblyavailable nitrogen atoms of the ring are optionally and independentlyfrom each other substituted with R^(2.2); and R^(2.1) is R^(2.1.a) andR^(2.1.a) is selected from among H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) is R^(2.1.1a)and R^(2.1.1.a) is selected from among aryl-, optionally substitutedindependently from each other with one, two or three residuesindependently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-, containingone, two, three or four heteroatoms selected independently from S, S(O),S(O)₂, O or and N, wherein carbon atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.1.1.1); wherein nitrogen atoms of the ring are optionally andindependently from each other substituted with one, two or threeR^(2.1.1.2); C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-, C₁₋₄-haloalkyl-O—and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independently selected fromamong O═, C₁₋₄-alkyl-, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-, H(O)C—,C₁₋₄-alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl;and R^(2.2) is R^(2.2.a) and R^(2.2.a) is independently selected fromamong H-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-.
 10. The compound of formula 1, according to claim 1,wherein R² is R^(2.m) and R^(2.m) is together with R⁴ and two adjacentcarbon atoms of the heteroaryl ring a 5- or 6-membered aryl orheteroaryl, containing one, two or three heteroatoms independentlyselected from among S, S(O), S(O)₂, O and N, wherein carbon atoms of thering are optionally and independently from each other substituted withone, two or three R^(2.1), wherein possibly available nitrogen atoms ofthe ring are optionally and independently from each other substitutedwith one, two or three R^(2.2); and R^(2.1) is R^(2.1.a) and R^(2.1.a)is selected from among H, halogen, NC—, O═, HO—, H-A-,H-A-C₁₋₄-alkylene-, R^(2.1.1)-A-, C₁₋₄-alkyl-A-, C₃₋₆-cycloalkyl-A-,C₁₋₄-haloalkyl-A-, R^(2.1.1)—C₁₋₄-alkylene-A-,C₁₋₄-alkyl-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-,C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)—C₁₋₄-alkylene-A-C₁₋₄-alkylene-, R^(2.1.1)-A-C₁₋₄-alkylene-,HO—C₁₋₄-alkylene-A-, HO—C₁₋₄-alkylene-A-C₁₋₄-alkylene-,C₁₋₄-alkyl-O—C₁₋₄-alkylene-A- andC₁₋₄-alkyl-O—C₁₋₄-alkylene-A-C₁₋₄-alkylene-; and R^(2.1.1) isR^(2.1.1.a) and R^(2.1.1.a) is selected from aryl-, optionallysubstituted independently from each other with one, two or threeresidues independently selected from R^(2.1.1.1); C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O or N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl-, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl; and R^(2.2) isR^(2.2.a) and R^(2.2.a) is independently selected from amongH-A-C₁₋₄-alkylene-, C₃₋₆-cycloalkyl-, C₁₋₄-alkyl-A-C₁₋₄-alkylene-,C₃₋₆-cycloalkyl-A-C₁₋₄-alkylene-, C₁₋₄-haloalkyl-A-C₁₋₄-alkylene-,R^(2.1.1)-A-C₁₋₄-alkylene-, C₁₋₄-alkyl-S(O)₂—, C₁₋₄-alkyl-C(O)— andR^(2.1.1)-A-.
 11. The compound of formula 1, according to claim 1,wherein R¹ is H, R³ is H or F, and R² and R⁴ are together with twoadjacent carbon atoms of the heteroaryl ring a 5- or 6-membered aryl,wherein the 5- or 6-membered aryl is optionally substituted by one ortwo residues selected from among halogen, —CN, C₅₋₁₀-heteroaryl-,containing one, two, three or four heteroatoms selected independentlyfrom S, S(O), S(O)₂, O and N, wherein carbon atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.1); wherein nitrogen atoms of the ring are optionallyand independently from each other substituted with one, two or threeR^(2.1.1.2); and C₅₋₁₀-heterocyclyl-, containing one, two, three or fourheteroatoms selected independently from S, S(O), S(O)₂, O and N and thering is fully or partially saturated, wherein carbon atoms of the ringare optionally and independently from each other substituted with one,two or three R^(2.1.1.1); wherein nitrogen atoms of the ring areoptionally and independently from each other substituted with one, twoor three R^(2.1.1.2); and R^(2.1.1.1) is independently selected fromamong halogen, HO—, O═, C₁₋₄-alkyl-, C₁₋₄-alkyl-O—, C₁₋₄-haloalkyl-,C₁₋₄-haloalkyl-O— and C₃₋₆-cycloalkyl-; and R^(2.1.1.2) is independentlyselected from among O═, C₁₋₄-haloalkyl-; C₃₋₆-cycloalkyl-,C₁₋₄-alkyl-O—C₁₋₄-alkyl, H(O)C—, C₁₋₄-alkyl-(O)C—,tetrahydrofuranylmethyl- and tetrahydropyranylmethyl, or salts thereof.12. A compound of formula 1′

wherein X, Y, R¹, R², R³ and R⁴ have the meaning of claim
 1. 13. Apharmaceutical composition, comprising a compound of formula 1 accordingto claim 1 or a pharmaceutically acceptable salt thereof.
 14. Thepharmaceutical composition according to claim 13 further comprising apharmaceutically active compound selected from among the groupconsisting of betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, CRTH2 inhibitors,5-LO-inhibitors, Histamine receptor antagonists, CCR9 antagonists andSYK-inhibitors, NE-inhibitors, MMP9 inhibitors and MMP12 inhibitors, orcombinations of two or three of the pharmaceutically active compound.